A family of intracellular CYSTEINE ENDOPEPTIDASES that play a role in regulating INFLAMMATION and APOPTOSIS. They specifically cleave peptides at a CYSTEINE amino acid that follows an ASPARTIC ACID residue. Caspases are activated by proteolytic cleavage of a precursor form to yield large and small subunits that form the enzyme. Since the cleavage site within precursors matches the specificity of caspases, sequential activation of precursors by activated caspases can occur.
Endogenous and exogenous compounds and that either inhibit CASPASES or prevent their activation.
One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.
A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 7; CASPASE 8; and CASPASE 10. Isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.
A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 9. Isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.
A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 3 and CASPASE 10. Several isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.
A subtype of caspases that contain long pro-domain regions that regulate the activation of the enzyme. The pro-domain regions contain protein-protein interaction motifs that can interact with specific signaling adaptor proteins such as DEATH DOMAIN RECEPTORS; DED SIGNALING ADAPTOR PROTEINS; and CARD SIGNALING ADAPTOR PROTEINS. Once activated, the initiator caspases can activate other caspases such as the EFFECTOR CASPASES.
Inhibitors of SERINE ENDOPEPTIDASES and sulfhydryl group-containing enzymes. They act as alkylating agents and are known to interfere in the translation process.
A long pro-domain caspase that contains a caspase recruitment domain in its pro-domain region. Caspase 9 is activated during cell stress by mitochondria-derived proapoptotic factors and by CARD SIGNALING ADAPTOR PROTEINS such as APOPTOTIC PROTEASE-ACTIVATING FACTOR 1. It activates APOPTOSIS by cleaving and activating EFFECTOR CASPASES.
A transfer RNA which is specific for carrying methionine to sites on the ribosomes. During initiation of protein synthesis, tRNA(f)Met in prokaryotic cells and tRNA(i)Met in eukaryotic cells binds to the start codon (CODON, INITIATOR).
Exogenous and endogenous compounds which inhibit CYSTEINE ENDOPEPTIDASES.
A codon that directs initiation of protein translation (TRANSLATION, GENETIC) by stimulating the binding of initiator tRNA (RNA, TRANSFER, MET). In prokaryotes, the codons AUG or GUG can act as initiators while in eukaryotes, AUG is the only initiator codon.
A subclass of caspases that contain short pro-domain regions. They are activated by the proteolytic action of INITIATOR CASPASES. Once activated they cleave a variety of substrates that cause APOPTOSIS.
A long pro-domain caspase that contains a death effector domain in its pro-domain region. Caspase 8 plays a role in APOPTOSIS by cleaving and activating EFFECTOR CASPASES. Activation of this enzyme can occur via the interaction of its N-terminal death effector domain with DEATH DOMAIN RECEPTOR SIGNALING ADAPTOR PROTEINS.
A long pro-domain caspase that contains a caspase recruitment domain in its pro-domain region. Activation of this enzyme can occur via the interaction of its caspase recruitment domain with CARD SIGNALING ADAPTOR PROTEINS. Caspase 2 plays a role in APOPTOSIS by cleaving and activating effector pro-caspases. Several isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.
Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme.
The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.
Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.
A process of GENETIC TRANSLATION whereby the formation of a peptide chain is started. It includes assembly of the RIBOSOME components, the MESSENGER RNA coding for the polypeptide to be made, INITIATOR TRNA, and PEPTIDE INITIATION FACTORS; and placement of the first amino acid in the peptide chain. The details and components of this process are unique for prokaryotic protein biosynthesis and eukaryotic protein biosynthesis.
An inhibitor of apoptosis protein that is translated by a rare cap-independent mechanism. It blocks caspase-mediated cellular destruction by inhibiting CASPASE 3; CASPASE 7; and CASPASE 9.
A conserved class of proteins that control APOPTOSIS in both VERTEBRATES and INVERTEBRATES. IAP proteins interact with and inhibit CASPASES, and they function as ANTI-APOPTOTIC PROTEINS. The protein class is defined by an approximately 80-amino acid motif called the baculoviral inhibitor of apoptosis repeat.
Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed)
A CARD signaling adaptor protein that plays a role in the mitochondria-stimulated apoptosis (APOPTOSIS, INTRINSIC PATHWAY). It binds to CYTOCHROME C in the CYTOSOL to form an APOPTOSOMAL PROTEIN COMPLEX and activates INITIATOR CASPASES such as CASPASE 9.
Membrane proteins encoded by the BCL-2 GENES and serving as potent inhibitors of cell death by APOPTOSIS. The proteins are found on mitochondrial, microsomal, and NUCLEAR MEMBRANE sites within many cell types. Overexpression of bcl-2 proteins, due to a translocation of the gene, is associated with follicular lymphoma.
A group of cytochromes with covalent thioether linkages between either or both of the vinyl side chains of protoheme and the protein. (Enzyme Nomenclature, 1992, p539)
A tumor necrosis factor receptor subtype found in a variety of tissues and on activated LYMPHOCYTES. It has specificity for FAS LIGAND and plays a role in regulation of peripheral immune responses and APOPTOSIS. Multiple isoforms of the protein exist due to multiple ALTERNATIVE SPLICING. The activated receptor signals via a conserved death domain that associates with specific TNF RECEPTOR-ASSOCIATED FACTORS in the CYTOPLASM.
Splitting the DNA into shorter pieces by endonucleolytic DNA CLEAVAGE at multiple sites. It includes the internucleosomal DNA fragmentation, which along with chromatin condensation, are considered to be the hallmarks of APOPTOSIS.
A long pro-domain caspase that contains a death effector domain in its pro-domain region. Activation of this enzyme can occur via the interaction of its N-terminal death effector domain with DEATH DOMAIN RECEPTOR SIGNALING ADAPTOR PROTEINS. Caspase 10 plays a role in APOPTOSIS by cleaving and activating EFFECTOR CASPASES. Several isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.
A long pro-domain caspase that has specificity for the precursor form of INTERLEUKIN-1BETA. It plays a role in INFLAMMATION by catalytically converting the inactive forms of CYTOKINES such as interleukin-1beta to their active, secreted form. Caspase 1 is referred as interleukin-1beta converting enzyme and is frequently abbreviated ICE.
A unique DNA sequence of a replicon at which DNA REPLICATION is initiated and proceeds bidirectionally or unidirectionally. It contains the sites where the first separation of the complementary strands occurs, a primer RNA is synthesized, and the switch from primer RNA to DNA synthesis takes place. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)
Cytochromes of the c type that are found in eukaryotic MITOCHONDRIA. They serve as redox intermediates that accept electrons from MITOCHONDRIAL ELECTRON TRANSPORT COMPLEX III and transfer them to MITOCHONDRIAL ELECTRON TRANSPORT COMPLEX IV.
ENDOPEPTIDASES which have a cysteine involved in the catalytic process. This group of enzymes is inactivated by CYSTEINE PROTEINASE INHIBITORS such as CYSTATINS and SULFHYDRYL REAGENTS.
A CELL LINE derived from human T-CELL LEUKEMIA and used to determine the mechanism of differential susceptibility to anti-cancer drugs and radiation.
Enzymes that catalyze the transfer of multiple ADP-RIBOSE groups from nicotinamide-adenine dinucleotide (NAD) onto protein targets, thus building up a linear or branched homopolymer of repeating ADP-ribose units i.e., POLY ADENOSINE DIPHOSPHATE RIBOSE.
The process by which a DNA molecule is duplicated.
The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.
Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.
A conserved A-T rich sequence which is contained in promoters for RNA polymerase II. The segment is seven base pairs long and the nucleotides most commonly found are TATAAAA.
The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability.
Extrachromosomal, usually CIRCULAR DNA molecules that are self-replicating and transferable from one organism to another. They are found in a variety of bacterial, archaeal, fungal, algal, and plant species. They are used in GENETIC ENGINEERING as CLONING VECTORS.
The small RNA molecules, 73-80 nucleotides long, that function during translation (TRANSLATION, GENETIC) to align AMINO ACIDS at the RIBOSOMES in a sequence determined by the mRNA (RNA, MESSENGER). There are about 30 different transfer RNAs. Each recognizes a specific CODON set on the mRNA through its own ANTICODON and as aminoacyl tRNAs (RNA, TRANSFER, AMINO ACYL), each carries a specific amino acid to the ribosome to add to the elongating peptide chains.
Enzymes that catalyze the transfer of hydroxymethyl or formyl groups. EC 2.1.2.
Multimeric protein complexes formed in the CYTOSOL that play a role in the activation of APOPTOSIS. They can occur when MITOCHONDRIA become damaged due to cell stress and release CYTOCHROME C. Cytosolic cytochrome C associates with APOPTOTIC PROTEASE-ACTIVATING FACTOR 1 to form the apoptosomal protein complex. The apoptosome signals apoptosis by binding to and activating specific INITIATOR CASPASES such as CASPASE 9.
A member of the Bcl-2 protein family that reversibly binds MEMBRANES. It is a pro-apoptotic protein that is activated by caspase cleavage.
A member of the Bcl-2 protein family and homologous partner of C-BCL-2 PROTO-ONCOGENE PROTEIN. It regulates the release of CYTOCHROME C and APOPTOSIS INDUCING FACTOR from the MITOCHONDRIA. Several isoforms of BCL2-associated X protein occur due to ALTERNATIVE SPLICING of the mRNA for this protein.
A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc.
Established cell cultures that have the potential to propagate indefinitely.
The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.
The largest of the three prokaryotic initiation factors with a molecular size of approximately 80 kD. It functions in the transcription initiation process by promoting the binding of formylmethionine-tRNA to the P-site of the 30S ribosome and by preventing the incorrect binding of elongator tRNA to the translation initiation site.
The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for VIRUS CULTIVATION and antitumor drug screening assays.
The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.
The parts of a macromolecule that directly participate in its specific combination with another molecule.
Physiologically inactive substances that can be converted to active enzymes.
Proteins that catalyze the unwinding of duplex DNA during replication by binding cooperatively to single-stranded regions of DNA or to short regions of duplex DNA that are undergoing transient opening. In addition DNA helicases are DNA-dependent ATPases that harness the free energy of ATP hydrolysis to translocate DNA strands.
The spatial arrangement of the atoms of a nucleic acid or polynucleotide that results in its characteristic 3-dimensional shape.
DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes.
Peptides composed of between two and twelve amino acids.
A large group of proteins that control APOPTOSIS. This family of proteins includes many ONCOGENE PROTEINS as well as a wide variety of classes of INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS such as CASPASES.
A signal-transducing adaptor protein that associates with TNF RECEPTOR complexes. It contains a death effector domain that can interact with death effector domains found on INITIATOR CASPASES such as CASPASE 8 and CASPASE 10. Activation of CASPASES via interaction with this protein plays a role in the signaling cascade that leads to APOPTOSIS.
Protein factors uniquely required during the initiation phase of protein synthesis in GENETIC TRANSLATION.
Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.
Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.
The biosynthesis of PEPTIDES and PROTEINS on RIBOSOMES, directed by MESSENGER RNA, via TRANSFER RNA that is charged with standard proteinogenic AMINO ACIDS.
A death domain receptor signaling adaptor protein that plays a role in signaling the activation of INITIATOR CASPASES such as CASPASE 2. It contains a death domain that is specific for RIP SERINE-THEONINE KINASES and a caspase-binding domain that binds to and activates CASPASES such as CASPASE 2.
Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.
A member of the bcl-2 protein family that plays a role in the regulation of APOPTOSIS. Two major isoforms of the protein exist due to ALTERNATIVE SPLICING of the BCL2L1 mRNA and are referred to as Bcl-XS and Bcl-XL.
The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.
Multicomponent ribonucleoprotein structures found in the CYTOPLASM of all cells, and in MITOCHONDRIA, and PLASTIDS. They function in PROTEIN BIOSYNTHESIS via GENETIC TRANSLATION.
Proteins found in any species of bacterium.
Proteins found in any species of virus.
A cell line derived from cultured tumor cells.
Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.
The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.
The sequential set of three nucleotides in TRANSFER RNA that interacts with its complement in MESSENGER RNA, the CODON, during translation in the ribosome.
An indolocarbazole that is a potent PROTEIN KINASE C inhibitor which enhances cAMP-mediated responses in human neuroblastoma cells. (Biochem Biophys Res Commun 1995;214(3):1114-20)
RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.
Transport proteins that carry specific substances in the blood or across cell membranes.
A transmembrane protein belonging to the tumor necrosis factor superfamily that was originally discovered on cells of the lymphoid-myeloid lineage, including activated T-LYMPHOCYTES and NATURAL KILLER CELLS. It plays an important role in immune homeostasis and cell-mediated toxicity by binding to the FAS RECEPTOR and triggering APOPTOSIS.
Intermediates in protein biosynthesis. The compounds are formed from amino acids, ATP and transfer RNA, a reaction catalyzed by aminoacyl tRNA synthetase. They are key compounds in the genetic translation process.
An in situ method for detecting areas of DNA which are nicked during APOPTOSIS. Terminal deoxynucleotidyl transferase is used to add labeled dUTP, in a template-independent manner, to the 3 prime OH ends of either single- or double-stranded DNA. The terminal deoxynucleotidyl transferase nick end labeling, or TUNEL, assay labels apoptosis on a single-cell level, making it more sensitive than agarose gel electrophoresis for analysis of DNA FRAGMENTATION.
Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.
Proteins prepared by recombinant DNA technology.
An enzyme that activates methionine with its specific transfer RNA. EC
The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.
Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.
A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.
A transmembrane-protein belonging to the TNF family of intercellular signaling proteins. It is a widely expressed ligand that activates APOPTOSIS by binding to TNF-RELATED APOPTOSIS-INDUCING LIGAND RECEPTORS. The membrane-bound form of the protein can be cleaved by specific CYSTEINE ENDOPEPTIDASES to form a soluble ligand form.
A protein of the annexin family isolated from human PLACENTA and other tissues. It inhibits cytosolic PHOSPHOLIPASE A2, and displays anticoagulant activity.
A prokaryotic initiation factor that plays a role in recycling of ribosomal subunits for a new round of translational initiation. It binds to 16S RIBOSOMAL RNA and stimulates the dissociation of vacant 70S ribosomes. It may also be involved in the preferential binding of initiator tRNA to the 30S initiation complex.
A flavoprotein that functions as a powerful antioxidant in the MITOCHONDRIA and promotes APOPTOSIS when released from the mitochondria. In mammalian cells AIF is released in response to pro-apoptotic protein members of the bcl-2 protein family. It translocates to the CELL NUCLEUS and binds DNA to stimulate CASPASE-independent CHROMATIN condensation.
A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (CODON, TERMINATOR). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, TRANSFER) complementary to all codons. These codons are referred to as unassigned codons (CODONS, NONSENSE).
Effective in the initiation of protein synthesis. The initiating methionine residue enters the ribosome as N-formylmethionyl tRNA. This process occurs in Escherichia coli and other bacteria as well as in the mitochondria of eucaryotic cells.
Cysteine proteinase found in many tissues. Hydrolyzes a variety of endogenous proteins including NEUROPEPTIDES; CYTOSKELETAL PROTEINS; proteins from SMOOTH MUSCLE; CARDIAC MUSCLE; liver; platelets; and erythrocytes. Two subclasses having high and low calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. This enzyme was formerly listed as EC
A promyelocytic cell line derived from a patient with ACUTE PROMYELOCYTIC LEUKEMIA. HL-60 cells lack specific markers for LYMPHOID CELLS but express surface receptors for FC FRAGMENTS and COMPLEMENT SYSTEM PROTEINS. They also exhibit phagocytic activity and responsiveness to chemotactic stimuli. (From Hay et al., American Type Culture Collection, 7th ed, pp127-8)
A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).
The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.
A peroxide derivative that has been used topically for BURNS and as a dermatologic agent in the treatment of ACNE and POISON IVY DERMATITIS. It is used also as a bleach in the food industry.
A long pro-domain caspase that contains a caspase recruitment domain in its pro-domain region. Caspase 12 is activated by pro-apoptotic factors that are released during cell stress and by CARD SIGNALING ADAPTOR PROTEINS. It activates APOPTOSIS by cleaving and activating EFFECTOR CASPASES.
The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.
The voltage difference, normally maintained at approximately -180mV, across the INNER MITOCHONDRIAL MEMBRANE, by a net movement of positive charge across the membrane. It is a major component of the PROTON MOTIVE FORCE in MITOCHONDRIA used to drive the synthesis of ATP.
The pathological process occurring in cells that are dying from irreparable injuries. It is caused by the progressive, uncontrolled action of degradative ENZYMES, leading to MITOCHONDRIAL SWELLING, nuclear flocculation, and cell lysis. It is distinct it from APOPTOSIS, which is a normal, regulated cellular process.
A family of serine proteinase inhibitors which are similar in amino acid sequence and mechanism of inhibition, but differ in their specificity toward proteolytic enzymes. This family includes alpha 1-antitrypsin, angiotensinogen, ovalbumin, antiplasmin, alpha 1-antichymotrypsin, thyroxine-binding protein, complement 1 inactivators, antithrombin III, heparin cofactor II, plasminogen inactivators, gene Y protein, placental plasminogen activator inhibitor, and barley Z protein. Some members of the serpin family may be substrates rather than inhibitors of SERINE ENDOPEPTIDASES, and some serpins occur in plants where their function is not known.
Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.
Diffusible gene products that act on homologous or heterologous molecules of viral or cellular DNA to regulate the expression of proteins.
Constituent composed of protein and phospholipid that is widely distributed in many tissues. It serves as a cofactor with factor VIIa to activate factor X in the extrinsic pathway of blood coagulation.
Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.
A sulfur-containing essential L-amino acid that is important in many body functions.
The rate dynamics in chemical or physical systems.
Serum glycoprotein produced by activated MACROPHAGES and other mammalian MONONUCLEAR LEUKOCYTES. It has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. Also known as TNF-alpha, it is only 30% homologous to TNF-beta (LYMPHOTOXIN), but they share TNF RECEPTORS.
Proteins encoded by the mitochondrial genome or proteins encoded by the nuclear genome that are imported to and resident in the MITOCHONDRIA.
A group of ribonucleotides (up to 12) in which the phosphate residues of each ribonucleotide act as bridges in forming diester linkages between the ribose moieties.
Elements of limited time intervals, contributing to particular results or situations.
A multi-domain mitochondrial membrane protein and member of the bcl-2 Protein family. Bak protein interacts with TUMOR SUPPRESSOR PROTEIN P53 and promotes APOPTOSIS.
The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.
The process by which two molecules of the same chemical composition form a condensation product or polymer.
A fractionated cell extract that maintains a biological function. A subcellular fraction isolated by ultracentrifugation or other separation techniques must first be isolated so that a process can be studied free from all of the complex side reactions that occur in a cell. The cell-free system is therefore widely used in cell biology. (From Alberts et al., Molecular Biology of the Cell, 2d ed, p166)
Proteins that originate from insect species belonging to the genus DROSOPHILA. The proteins from the most intensely studied species of Drosophila, DROSOPHILA MELANOGASTER, are the subject of much interest in the area of MORPHOGENESIS and development.
The major sequence-specific DNA-binding component involved in the activation of transcription of RNA POLYMERASE II. It was originally described as a complex of TATA-BOX BINDING PROTEIN and TATA-BINDING PROTEIN ASSOCIATED FACTORS. It is now know that TATA BOX BINDING PROTEIN-LIKE PROTEINS may take the place of TATA-box binding protein in the complex.
Intracellular signaling adaptor proteins that bind to the cytoplasmic death domain region found on DEATH DOMAIN RECEPTORS. Many of the proteins in this class take part in intracellular signaling from TUMOR NECROSIS FACTOR RECEPTORS.
The relationship between the dose of an administered drug and the response of the organism to the drug.
The process of cleaving a chemical compound by the addition of a molecule of water.
A family of cell surface receptors that signal via a conserved domain that extends into the cell CYTOPLASM. The conserved domain is referred to as a death domain due to the fact that many of these receptors are involved in signaling APOPTOSIS. Several DEATH DOMAIN RECEPTOR SIGNALING ADAPTOR PROTEINS can bind to the death domains of the activated receptors and through a complex series of interactions activate apoptotic mediators such as CASPASES.
Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.
The origin recognition complex is a multi-subunit DNA-binding protein that initiates DNA REPLICATION in eukaryotes.
The combination of two or more different factors in the production of cancer.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.
Intracellular fluid from the cytoplasm after removal of ORGANELLES and other insoluble cytoplasmic components.
Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include SINGLET OXYGEN; SUPEROXIDES; PEROXIDES; HYDROXYL RADICAL; and HYPOCHLOROUS ACID. They contribute to the microbicidal activity of PHAGOCYTES, regulation of signal transduction and gene expression, and the oxidative damage to NUCLEIC ACIDS; PROTEINS; and LIPIDS.
Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)
Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility.
Eukaryotic initiation factor of protein synthesis. In higher eukaryotes the factor consists of three subunits: alpha, beta, and gamma. As initiation proceeds, eIF-2 forms a ternary complex with Met-tRNAi and GTP.
Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes.
Short sequences (generally about 10 base pairs) of DNA that are complementary to sequences of messenger RNA and allow reverse transcriptases to start copying the adjacent sequences of mRNA. Primers are used extensively in genetic and molecular biology techniques.
Substances that inhibit or prevent the proliferation of NEOPLASMS.
A family of serine endopeptidases found in the SECRETORY GRANULES of LEUKOCYTES such as CYTOTOXIC T-LYMPHOCYTES and NATURAL KILLER CELLS. When secreted into the intercellular space granzymes act to eliminate transformed and virus-infected host cells.
Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity.
A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement.
Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.
Dried aged bark of a buckthorn, Frangula purshiana (FRANGULA), that contains the anthraquinone EMODIN and cascarosides. It is used as a laxative (CATHARTICS).
A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.
A eukaryotic initiation factor that binds to 40S ribosomal subunits. Although initially considered a "non-essential" factor for eukaryotic transcription initiation, eukaryotic initiation factor-1 is now thought to play an important role in localizing RIBOSOMES at the initiation codon of MRNA.
Glycoproteins found on the membrane or surface of cells.
Proteins and peptides that are involved in SIGNAL TRANSDUCTION within the cell. Included here are peptides and proteins that regulate the activity of TRANSCRIPTION FACTORS and cellular processes in response to signals from CELL SURFACE RECEPTORS. Intracellular signaling peptide and proteins may be part of an enzymatic signaling cascade or act through binding to and modifying the action of other signaling factors.
Nuclear phosphoprotein encoded by the p53 gene (GENES, P53) whose normal function is to control CELL PROLIFERATION and APOPTOSIS. A mutant or absent p53 protein has been found in LEUKEMIA; OSTEOSARCOMA; LUNG CANCER; and COLORECTAL CANCER.
Any DNA sequence capable of independent replication or a molecule that possesses a REPLICATION ORIGIN and which is therefore potentially capable of being replicated in a suitable cell. (Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)
The sequential correspondence of nucleotides in one nucleic acid molecule with those of another nucleic acid molecule. Sequence homology is an indication of the genetic relatedness of different organisms and gene function.
A genus of small, two-winged flies containing approximately 900 described species. These organisms are the most extensively studied of all genera from the standpoint of genetics and cytology.
Deoxyribonucleic acid that makes up the genetic material of bacteria.
A process of GENETIC TRANSLATION, when an amino acid is transferred from its cognate TRANSFER RNA to the lengthening chain of PEPTIDES.
Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake.
The arrangement of two or more amino acid or base sequences from an organism or organisms in such a way as to align areas of the sequences sharing common properties. The degree of relatedness or homology between the sequences is predicted computationally or statistically based on weights assigned to the elements aligned between the sequences. This in turn can serve as a potential indicator of the genetic relatedness between the organisms.
Cell surface receptors that bind TUMOR NECROSIS FACTORS and trigger changes which influence the behavior of cells.
A short pro-domain caspase that is almost exclusively expressed in the EPIDERMIS and may play a role in the differentiation of epidermal KERATINOCYTES.
Use of restriction endonucleases to analyze and generate a physical map of genomes, genes, or other segments of DNA.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in enzyme synthesis.
Tumor necrosis factor receptor family members that are widely expressed and play a role in regulation of peripheral immune responses and APOPTOSIS. The receptors are specific for TNF-RELATED APOPTOSIS-INDUCING LIGAND and signal via conserved death domains that associate with specific TNF RECEPTOR-ASSOCIATED FACTORS in the CYTOPLASM.
An APOPTOSIS-regulating protein that is structurally related to CASPASE 8 and competes with CASPASE 8 for binding to FAS ASSOCIATED DEATH DOMAIN PROTEIN. Two forms of CASP8 and FADD-like apoptosis regulating protein exist, a long form containing a caspase-like enzymatically inactive domain and a short form which lacks the caspase-like domain.
A circumscribed benign epithelial tumor projecting from the surrounding surface; more precisely, a benign epithelial neoplasm consisting of villous or arborescent outgrowths of fibrovascular stroma covered by neoplastic cells. (Stedman, 25th ed)
Immunologic method used for detecting or quantifying immunoreactive substances. The substance is identified by first immobilizing it by blotting onto a membrane and then tagging it with labeled antibodies.
A method for determining the sequence specificity of DNA-binding proteins. DNA footprinting utilizes a DNA damaging agent (either a chemical reagent or a nuclease) which cleaves DNA at every base pair. DNA cleavage is inhibited where the ligand binds to DNA. (from Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)
Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA-binding subunits: NF-kappa B1 and relA.
Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane.
Any member of the group of ENDOPEPTIDASES containing at the active site a serine residue involved in catalysis.
A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.
Microscopy of specimens stained with fluorescent dye (usually fluorescein isothiocyanate) or of naturally fluorescent materials, which emit light when exposed to ultraviolet or blue light. Immunofluorescence microscopy utilizes antibodies that are labeled with fluorescent dye.
Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.
The B-cell leukemia/lymphoma-2 genes, responsible for blocking apoptosis in normal cells, and associated with follicular lymphoma when overexpressed. Overexpression results from the t(14;18) translocation. The human c-bcl-2 gene is located at 18q24 on the long arm of chromosome 18.
All of the processes involved in increasing CELL NUMBER including CELL DIVISION.
Chemical reaction in which monomeric components are combined to form POLYMERS (e.g., POLYMETHYLMETHACRYLATE).
The complex series of phenomena, occurring between the end of one CELL DIVISION and the end of the next, by which cellular material is duplicated and then divided between two daughter cells. The cell cycle includes INTERPHASE, which includes G0 PHASE; G1 PHASE; S PHASE; and G2 PHASE, and CELL DIVISION PHASE.
Derivatives of phosphatidic acids in which the phosphoric acid is bound in ester linkage to a serine moiety. Complete hydrolysis yields 1 mole of glycerol, phosphoric acid and serine and 2 moles of fatty acids.
Chemical compound used to initiate polymerization of dental resins by the use of DENTAL CURING LIGHTS. It absorbs UV light and undergoes decomposition into free radicals that initiate polymerization process of the resins in the mix. Each photoinitiator has optimum emission spectrum and intensity for proper curing of dental materials.
A subgroup of mitogen-activated protein kinases that activate TRANSCRIPTION FACTOR AP-1 via the phosphorylation of C-JUN PROTEINS. They are components of intracellular signaling pathways that regulate CELL PROLIFERATION; APOPTOSIS; and CELL DIFFERENTIATION.
The methyl ester of methacrylic acid. It polymerizes easily to form POLYMETHYL METHACRYLATE. It is used as a bone cement.
A family of serine-threonine kinases that plays a role in intracellular signal transduction by interacting with a variety of signaling adaptor proteins such as CRADD SIGNALING ADAPTOR PROTEIN; TNF RECEPTOR-ASSOCIATED FACTOR 2; and TNF RECEPTOR-ASSOCIATED DEATH DOMAIN PROTEIN. Although they were initially described as death domain-binding adaptor proteins, members of this family may contain other protein-binding domains such as those involving caspase activation and recruitment.
Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.
The methyl esters of methacrylic acid that polymerize easily and are used as tissue cements, dental materials, and absorbent for biological substances.
Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.
The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.
A broad category of carrier proteins that play a role in SIGNAL TRANSDUCTION. They generally contain several modular domains, each of which having its own binding activity, and act by forming complexes with other intracellular-signaling molecules. Signal-transducing adaptor proteins lack enzyme activity, however their activity can be modulated by other signal-transducing enzymes
Small double-stranded, non-protein coding RNAs (21-31 nucleotides) involved in GENE SILENCING functions, especially RNA INTERFERENCE (RNAi). Endogenously, siRNAs are generated from dsRNAs (RNA, DOUBLE-STRANDED) by the same ribonuclease, Dicer, that generates miRNAs (MICRORNAS). The perfect match of the siRNAs' antisense strand to their target RNAs mediates RNAi by siRNA-guided RNA cleavage. siRNAs fall into different classes including trans-acting siRNA (tasiRNA), repeat-associated RNA (rasiRNA), small-scan RNA (scnRNA), and Piwi protein-interacting RNA (piRNA) and have different specific gene silencing functions.
The two lipoprotein layers in the MITOCHONDRION. The outer membrane encloses the entire mitochondrion and contains channels with TRANSPORT PROTEINS to move molecules and ions in and out of the organelle. The inner membrane folds into cristae and contains many ENZYMES important to cell METABOLISM and energy production (MITOCHONDRIAL ATP SYNTHASE).
Nuclear matrix proteins that are structural components of the NUCLEAR LAMINA. They are found in most multicellular organisms.
An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.
Proteins whose abnormal expression (gain or loss) are associated with the development, growth, or progression of NEOPLASMS. Some neoplasm proteins are tumor antigens (ANTIGENS, NEOPLASM), i.e. they induce an immune reaction to their tumor. Many neoplasm proteins have been characterized and are used as tumor markers (BIOMARKERS, TUMOR) when they are detectable in cells and body fluids as monitors for the presence or growth of tumors. Abnormal expression of ONCOGENE PROTEINS is involved in neoplastic transformation, whereas the loss of expression of TUMOR SUPPRESSOR PROTEINS is involved with the loss of growth control and progression of the neoplasm.
An enzyme that activates alanine with its specific transfer RNA. EC
Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included.
That portion of the electromagnetic spectrum immediately below the visible range and extending into the x-ray frequencies. The longer wavelengths (near-UV or biotic or vital rays) are necessary for the endogenous synthesis of vitamin D and are also called antirachitic rays; the shorter, ionizing wavelengths (far-UV or abiotic or extravital rays) are viricidal, bactericidal, mutagenic, and carcinogenic and are used as disinfectants.
Polymerized methyl methacrylate monomers which are used as sheets, moulding, extrusion powders, surface coating resins, emulsion polymers, fibers, inks, and films (From International Labor Organization, 1983). This material is also used in tooth implants, bone cements, and hard corneal contact lenses.
Synthetic or naturally occurring substances related to coumarin, the delta-lactone of coumarinic acid.
Thin structures that encapsulate subcellular structures or ORGANELLES in EUKARYOTIC CELLS. They include a variety of membranes associated with the CELL NUCLEUS; the MITOCHONDRIA; the GOLGI APPARATUS; the ENDOPLASMIC RETICULUM; LYSOSOMES; PLASTIDS; and VACUOLES.
Polymers made up of a few (2-20) nucleotides. In molecular genetics, they refer to a short sequence synthesized to match a region where a mutation is known to occur, and then used as a probe (OLIGONUCLEOTIDE PROBES). (Dorland, 28th ed)
A human cell line established from a diffuse histiocytic lymphoma (HISTIOCYTIC LYMPHOMA, DIFFUSE) and displaying many monocytic characteristics. It serves as an in vitro model for MONOCYTE and MACROPHAGE differentiation.
The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.
A group of transfer RNAs which are specific for carrying each one of the 20 amino acids to the ribosome in preparation for protein synthesis.
A species of DELTAPAPILLOMAVIRUS infecting cattle.
A species of fruit fly much used in genetics because of the large size of its chromosomes.
The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.
Deoxyribonucleic acid that makes up the genetic material of viruses.

Caspase-1 (interleukin-1beta-converting enzyme) is inhibited by the human serpin analogue proteinase inhibitor 9. (1/57)

The regulation of caspases, cysteine proteinases that cleave their substrates after aspartic residues, is poorly understood, even though they are involved in tightly regulated cellular processes. The recently discovered serpin analogue proteinase inhibitor 9 (PI9) is unique among human serpin analogues in that it has an acidic residue in the putative specificity-determining position of the reactive-site loop. We measured the ability of PI9 to inhibit the amidolytic activity of several caspases. The hydrolysis of peptide substrates by caspase-1 (interleukin-1beta-converting enzyme), caspase-4 and caspase-8 is inhibited by PI9 in a time-dependent manner. The rate of reaction of caspase-1 with PI9, as well as the rate of substrate hydrolysis of the initial caspase-PI9 complex, shows a hyperbolic dependence on the concentration of PI9, indicative of a two-step kinetic mechanism for inhibition with an apparent second-order rate constant of 7x10(2) M(-1).s(-1). The hydrolysis of a tetrapeptide substrate by caspase-3 is not inhibited by PI9. The complexes of caspase-1 and caspase-4 with PI9 can be immunoprecipitated but no complex with caspase-3 can be detected. No complex can be immunoprecipitated if the active site of the caspase is blocked with a covalent inhibitor. These results show that PI9 is an inhibitor of caspase-1 and to a smaller extent caspase-4 and caspase-8, but not of the more distantly related caspase-3. PI9 is the first example of a human serpin analogue that inhibits members of this class of cysteine proteinases.  (+info)

Cytokine regulation of human intestinal primary epithelial cell susceptibility to Fas-mediated apoptosis. (2/57)

The regulatory mechanisms of nontransformed intestinal epithelial cell apoptosis have not been thoroughly investigated. We determined the susceptibility and mechanism of Fas-mediated apoptosis in nontransformed human intestinal epithelial cells (HIPEC) in the presence and absence of inflammatory cytokines. Despite ample expression of Fas, HIPEC were relatively insensitive to Fas-mediated apoptosis in that agonist anti-Fas antibody (CH11) induced a <25% increase in HIPEC apoptosis. Pretreatment of HIPEC with interferon (IFN)-gamma, but not tumor necrosis factor-alpha or granulocyte-macrophage colony-stimulating factor, significantly increased CH11-induced apoptosis of these cells without increasing Fas expression. Increased apoptosis correlated with increased caspase 3 activation but not expression of procaspase 3. Also, there was a significant delay in the onset of Fas-mediated apoptosis in HIPEC, which correlated with the generation of an activated caspase 3 p22/20 subunit. HIPEC required both initiator caspases 8 and 9 activity but expressed significantly less of the zymogen form of these caspases than did control cells. IFN-gamma-mediated sensitization of HIPEC occurred upstream of caspase 9 activation and correlated with a small increase in procaspase 8 expression (<1-fold increase) and a significant increase in expression of an intermediate form (p35) of caspase 4 (3.3-fold increase).  (+info)

Fully automated ab initio protein structure prediction using I-SITES, HMMSTR and ROSETTA. (3/57)

MOTIVATION: The Monte Carlo fragment insertion method for protein tertiary structure prediction (ROSETTA) of Baker and others, has been merged with the I-SITES library of sequence structure motifs and the HMMSTR model for local structure in proteins, to form a new public server for the ab initio prediction of protein structure. The server performs several tasks in addition to tertiary structure prediction, including a database search, amino acid profile generation, fragment structure prediction, and backbone angle and secondary structure prediction. Meeting reasonable service goals required improvements in the efficiency, in particular for the ROSETTA algorithm. RESULTS: The new server was used for blind predictions of 40 protein sequences as part of the CASP4 blind structure prediction experiment. The results for 31 of those predictions are presented here. 61% of the residues overall were found in topologically correct predictions, which are defined as fragments of 30 residues or more with a root-mean-square deviation in superimposed alpha carbons of less than 6A. HMMSTR 3-state secondary structure predictions were 73% correct overall. Tertiary structure predictions did not improve the accuracy of secondary structure prediction.  (+info)

Interferon-gamma-induced sensitization of colon carcinomas to ZD9331 targets caspases, downstream of Fas, independent of mitochondrial signaling and the inhibitor of apoptosis survivin. (4/57)

We have demonstrated previously a Fas-dependent component in thymineless death of human colon carcinoma cells. Importantly, the cytotoxic effects of thymidine deprivation induced by 5-fluorouracil (FUra) combined with leucovorin (LV) was enhanced by IFN-gamma, and the synergism was shown to be dependent on Fas, FUra-induced DNA damage, and independent of p53. Subsequently we examined the potential for synergistic interactions between IFN-gamma and the specific thymidylate synthase inhibitor, ZD9331. IFN-gamma sensitized colon carcinomas to ZD9331-induced apoptosis and loss in clonogenic survival, also dependent on ZD9331-induced DNA damage, independent of p53. Synergism occurred in HCT116, demonstrating previously RNA-mediated FUra/LV cytotoxicity that could not be potentiated by IFN-gamma. Manipulation of the Fas death receptor pathway from the level of the receptor (Nok1/Nok2, Fas overexpression, and DN-FADD) to the mitochondria (Bcl-xL and Bcl-2) did not modulate ZD9331 +/- IFN-gamma-induced cytotoxicity in HT29, with the exception that Nok1/Nok2-blocking antibodies partially protected HT29 from the cytotoxic activity of ZD9331 alone. However, IFN-gamma alone (but not ZD9331) up-regulated the expression of caspases -3, -4, -7, and -8, and in combination with ZD9331 demonstrated enhanced caspase activation and cleavage of poly(ADP-ribose) polymerase that was not prevented by overexpression of Bcl-2. Additionally, IFN-gamma increased the activity of the proteasome in HT29, leading to selective down-regulation of the antiapoptotic protein survivin, whereas simultaneously increasing Fas expression. However, reduction in the survivin:Fas ratio by transfection of survivin small interfering RNA and/or overexpression of Fas did not affect sensitivity of HT29 to ZD9331 +/- IFN-gamma. Data demonstrate that IFN-gamma combined with ZD9331 is synergistic in additional cell lines that demonstrate RNA-mediated FUra/LV cytotoxicity, and that a major target of interaction is at the level of caspases, downstream of Fas, and independent of involvement of either the mitochondria or survivin.  (+info)

Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. (5/57)

Recent studies have suggested that neuronal death in Alzheimer's disease or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Although caspase-12 has been implicated in ER stress-induced apoptosis and amyloid-beta (Abeta)-induced apoptosis in rodents, it is controversial whether similar mechanisms operate in humans. We found that human caspase-4, a member of caspase-1 subfamily that includes caspase-12, is localized to the ER membrane, and is cleaved when cells are treated with ER stress-inducing reagents, but not with other apoptotic reagents. Cleavage of caspase-4 is not affected by overexpression of Bcl-2, which prevents signal transduction on the mitochondria, suggesting that caspase-4 is primarily activated in ER stress-induced apoptosis. Furthermore, a reduction of caspase-4 expression by small interfering RNA decreases ER stress-induced apoptosis in some cell lines, but not other ER stress-independent apoptosis. Caspase-4 is also cleaved by administration of Abeta, and Abeta-induced apoptosis is reduced by small interfering RNAs to caspase-4. Thus, caspase-4 can function as an ER stress-specific caspase in humans, and may be involved in pathogenesis of Alzheimer's disease.  (+info)

Labile zinc and zinc transporter ZnT4 in mast cell granules: role in regulation of caspase activation and NF-kappaB translocation. (6/57)

The granules of mast cells and other inflammatory cells are known to be rich in zinc (Zn), a potent caspase inhibitor. The functions of granular Zn, its mechanism of uptake, and its relationship to caspase activation in apoptosis are unclear. The granules of a variety of mast cell types fluoresced intensely with the Zn-specific fluorophore Zinquin, and fluorescence was quenched by functional depletion of Zn using a membrane-permeable Zn chelator N, N, N', N'-tetrakis (2-pyridyl-methyl)ethylenediamine (TPEN). Zn levels were also depleted by various mast cell activators, including IgE/anti-IgE, and Zn was rapidly replenished during subsequent culture, suggesting an active uptake mechanism. In support of the latter, mast cells contained high levels of the vesicular Zn transporter ZnT(4), especially in the more apical granules. Immunofluorescence and immunogold labeling studies revealed significant pools of procaspase-3 and -4 in mast cell granules and their release during degranulation. Functional depletion of Zn by chelation with TPEN, but not by degranulation, resulted in greatly increased susceptibility of mast cells to toxin-induced caspase activation, as detected using a fluorogenic substrate assay. Release of caspases during degranulation was accompanied by a decreased susceptibility to toxins. Zn depletion by chelation, but not by degranulation, also resulted in nuclear translocation of the antiapoptotic, proinflammatory transcription factor NF-kappaB. These findings implicate a role for ZnT(4) in mast cell Zn homeostasis and suggest that granule pools of Zn may be distinct from those regulating activation of procaspase-3 and NF-kappaB.  (+info)

Altered patterns of gene expression specific to thoracic aortic aneurysms: microarray analysis of surgically resected specimens. (7/57)

Changes in the expression levels of several genes have been described in aortic aneurysm specimens, however, the spectrum of diverse molecular alterations remains to be elucidated. We attempted to identify key molecules that modulate the pathogenesis of aortic aneurysm, using a complimentary DNA microarray carrying approximately 13,000 human genes. Segments of thoracic aortic aneurysms (TAA) and adjacent normal thoracic aortic tissues without aneurysmal changes (NTA) were obtained from 20 patients undergoing graft surgery. RNA obtained from five pairs of TAA and NTA samples was compared to determine aneurysm-specific alterations using microarray. Further, the expression levels of several genes of interest were verified in the remaining specimens by real-time reverse transcription-polymerase chain reaction (RT-PCR). In microarray assays, several types of the matrix metalloproteinases were upregulated as reported previously. Also, 220 genes suggested to be involved in protein degradation, inflammation, apoptosis, stress response, intracellular signaling, and other processes were significantly upregulated. Many of these genes have not been previously implicated in cardiovascular disease. The real time RT-PCR independently confirmed that the expression levels of MMP-2, MMP-9, ADAMTS-1, and caspase 4 were consistently increased in TAA. The results indicate that many genes are involved in a complicated manner in the pathogenesis of TAA. Investigation of these genes will help clarify the pathogenesis of this disease, and may lead to the discovery of novel therapeutic targets.  (+info)

Proteomics analysis of H-RAS-mediated oncogenic transformation in a genetically defined human ovarian cancer model. (8/57)

RAS is a small GTP binding protein mutated in approximately 30% human cancer. Despite its important role in the initiation and progression of human cancer, the underlying mechanism of RAS-induced human epithelial transformation remains elusive. In this study, we probe the cellular and molecular mechanisms of RAS-mediated transformation, by profiling two human ovarian epithelial cell lines. One cell line was immortalized with SV40 T/t antigens and the human catalytic subunit of telomerase (T29), while the second cell line was transformed with an additional oncogenic ras(V12) allele (T29H). In total, 32 proteins associated with RAS-mediated transformation have been identified using peptide mass fingerprinting. These protein targets are involved in several cellular pathways, including metabolism, redox balance, calcium signaling, apoptosis, and cellular methylation. One such target, the 40 kDa procaspase 4 is significantly upregulated at the protein level in RAS-transformed T29H cells, related directly to signaling through MEK, but not PI3 kinase. Cellular caspase 4 activity is, however, suppressed in the T29H cells, suggesting that the maturation process of caspase 4 is abrogated in RAS-transformed T29H cells. Consistent with this notion, transformed T29H cells were less susceptible to the toxic effects of anti-Fas antibody than were immortalized, nontransformed T29 cells, associated with less activation of caspase 4. This study demonstrates that functional proteomic analysis of a genetically defined cancer model provides a powerful approach toward systematically identifying cellular targets associated with oncogenic transformation.  (+info)

It has been known that apoptotic morphological changes are observed in cell death caused by ER stress (Imaizumi et al., 2001). Caspases are activated to transmit apoptotic signals transcending the difference in species (Alnemri et al., 1996). In rodents, caspase-12 mediates apoptosis specifically in response to ER stress (Nakagawa et al., 2000). Although human caspase-12 gene is transcribed into mRNA, mature caspase-12 protein would not be produced, because the gene is interrupted by frame shift and premature stop codon (Fischer et al., 2002). Furthermore, it contains amino acid substitution in the critical site, which leads to loss of function in several caspases (Fischer et al., 2002). Thus, human caspase-12 does not seem to function in ER stress-induced apoptosis, and some other caspases with similar structure might substitute functionally for caspase-12 in humans. The caspase-12 gene is located within a region where caspase-1/ICE subfamily genes cluster (caspases 1, 4, 5, 12 in human and ...
Mouse anti Human caspase-14, clone 4C9 recognizes human caspase-14, a 242 amino acid ~28 kDa non-apoptotic caspase which exists as a
Conducting the trials in U.S. and Europe will allow Company to access the physicians that have worked with REOLYSIN in head and neck cancers.
REOLYSIN ingezet als vaccin, bereikt goede resultaten bij soft sarcomas. Aldus een kleinschalige fase II trial. Artikel update 15 juli 2012
Physiological roles of ASK1-mediated signal transduction in oxidative stress- and endoplasmic reticulum stress-induced apoptosis: advanced findings from ASK1 knockout mice ...
BioAssay record AID 513048 submitted by ChEMBL: Inhibition of human caspase-3-mediated apoptosis assessed as Ac-DEVD-7-amino-4-methylcoumarin cleavage product at 100 uM by fluorescence assay.
October 23,2007- Oncolytics Biotech Inc. Announces Approval for U.K. Clinical Trial Investigating REOLYSIN(R) in Combination with Cyclophosphamide.
Oncolytics Biotech(R) Inc. Announces Positive Results of U.K. Phase II REOLYSIN(R) and Radiation Combination Clinical Trial CALGARY, April 7 - Oncolytics Biotec
Acts as a positive regulator of T-cell maturation and inflammatory function. Required for several functions of T-cells, in both the CD4(+) and the CD8(+) compartments and this includes expression of cell surface markers of activation, proliferation, and cytokine production in response to specific or non-specific stimulation (By similarity). Enhances NK cell cytotoxicity by positively regulating polarization of microtubule-organizing center (MTOC) to cytotoxic synapse, lytic granule transport along microtubules, and dynein-mediated clustering to MTOC (PubMed:25762780). Interacts with HSPA5 and stabilizes the interaction between HSPA5 and ERN1, leading to suppression of ERN1-induced JNK activation and endoplasmic reticulum stress-induced apoptosis (PubMed:21289099).
This confimatory, small run-in study will investigate pelareorep [Reolysin] in combination with gemcitabine and cisplatin in pre-operative patients with
Technology Networks is an internationally recognised publisher that provides access to the latest scientific news, products, research, videos and posters.
Best in Show. Tracheal Regeneration by an Artificial Trachea with Human iPS Cell-Derived Multi-Ciliated Airway Cells. SP 343 Authors: K. Omori, M. Yamashita, I. Tateya, H. Okuyama. Best Basic Science. Endoplasmic Reticulum Stress-Induced Apoptosis and Necroptosis in Auditory Cells. SP 374. Authors: A. Kishino, K. Hayashi, T. Ohshima. Honorable Mention in Each Specialty. Business of Medicine/Practice Management. Reducing No-Show Rates with Implementation of a Phone Call Prior to Appointments: Cost-Saving, Schedule Optimizing, and Access Enhancing Intervention. SP 104 Authors: B. Hopkins, J. Meleca. Endocrine Surgery. Quality of Life in Obese Patients after Thyroidectomy for Goiter. SP 116 Authors: C. Shires, N. Beckmann, F. Vieira. Facial Plastic and Reconstructive Surgery. Labia Myocutaneous Free Flap: Cadaveric Study of a Novel Free Flap. SP 128 Authors: J. Rosenberg, M. Gray, B. Miles, B. Barbe. General Otolaryngology. Academic Productivity of Otolaryngologists in the Veterans Health ...
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
Reovirus Serotype 3 - Dearing Strain (REOLYSIN®) is a naturally occurring, ubiquitous, non-enveloped human reovirus. Its primary mode of activity is to infect and selectively target tumors with activating Ras pathway mutations. Up to 70% of pancreatic cancers have activating Ras pathway mutations and/ or over-expressions.. This is an open label, Phase 1b study of REOLYSIN® and chemotherapy in combination with pembrolizumab in patients with advanced (unresectable or metastatic) histologically confirmed pancreatic adenocarcinoma that progressed after (or did not tolerate) first-line therapy. It is thought that Reovirus when combined with chemotherapy would lead to increased viral replication and oncolysis preferentially in RAS activated tumors, with resulting immunogenic response than can be further enhanced by checkpoint inhibition using pembrolizumab. The study is designed to characterize the efficacy and safety of REOLYSIN® given intravenously in combination with one of the three ...
OncologyPRO is the home of ESMOs educational & scientific resources, with exclusive content for ESMO members such as ESMOs Congresses webcasts,
A short pro-domain caspase that plays an effector Role in Apoptosis. It is activated by Initiator Caspases such as Caspase 3 and Caspase 10. Several Isoforms of this protein exist due to multiple Alternative Splicing of its Messenger RNA ...
http://cancerGRACE.org/... Dr. Julie Brahmer reviews science and early trial results for immunotherapies for lung cancer ranging from cancer vaccines to anti-cancer viruses.
C/EBP homologous protein (CHOP), known also as DNA damage-inducible transcript 3 and as growth arrest and DNA damage-inducible protein 153 (GADD153), is induced in response to certain stressors. CHOP is universally acknowledged as a main conduit to endoplasmic reticulum stress-induced apoptosis. Ongoing research established the existence of CHOP-mediated apoptosis signaling networks, for which novel downstream targets are still being determined. However, there are studies that contradict this notion and assert that apoptosis is not the only mechanism by which CHOP plays in the development of pathologies. In this review, insights into the roles of CHOP in pathophysiology are summarized at the molecular and cellular levels. We further focus on the newest advances that implicate CHOP in human diseases including cancer, diabetes, neurodegenerative disorders, and notably, fibrosis.
The hazardous effects of herbicides are well known; however, their effects on the reproductive system remain unclear. In this study, we demonstrated the anti-proliferative effects of dinitramine (DN) on immature murine testicular cell lines (Leydig and Sertoli cells) mediated via endoplasmic reticulum (ER) stress-induced calcium dysregulation in the cytosol and mitochondria. The results demonstrated that the viability and proliferation of DN-treated TM3 and TM4 cells decreased significantly, eve
Gözüaçık, Devrim and Bialik, S. and Raveh, T. and Mitou, Geraldine and Shohat, G. and Sabanay, H. and Mizushima, N. and Yoshimori, T. and Kimchi, A. (2008) DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death. Cell Death and Differentiation, 15 (12). pp. 1875-1886. ISSN 1350-9047 / 1476-5403 ...
Plant cells, like cells from other kingdoms, have the ability to self-destruct in a genetically controlled manner. This process is defined as Programmed Cell Death (PCD). PCD can be triggered by various stimuli in plants including by endoplasmic reticulum (ER) stress. Research in the past two decades discovered that disruption of protein homeostasis in the endoplasmic reticulum (ER) could cause ER stress, which when prolonged/unresolved leads cells into PCD. ER stress-induced PCD is part of several plant processes, for instance, drought and heat stress have been found to elicit ER stress-induced PCD. Despite the importance of ER stress-induced PCD in plants, its regulation remains largely unknown, when compared with its counterpart in animal cells. In mammalian cells, several pro-apoptotic proteases called caspases were found to play a crucial role in ER stress-induced PCD. Over the past decade, several key proteases with caspase-like enzymatic activity have been discovered in plants and implicated in
Aging is the main risk factor for the development of idiopathic pulmonary fibrosis (IPF), a progressive and usually lethal lung disorder. Although the pathogenic mechanisms are uncertain, endoplasmic reticulum (ER) stress and impaired proteostasis that have been linked with aging are strongly associated with the pathogenesis of IPF. Using the Atg4b-deficient mice as a model, that partially reproduces the autophagy deficient conditions reported in aging and IPF lungs, we show for the first time how autophagy impairment and ER stress induction, contribute simultaneously to development of lung fibrosis in vivo. Increased expression of ER stress markers, inflammation and apoptosis of alveolar epithelial cells were observed in Atg4b-deficient mice compared to WT mice, when treated with the ER stress inducer tunicamycin. After tunicamycin treatment, Atg4b null lungs showed accumulation of its substrate LC3-I, demonstrating that these mice failed to induce autophagy despite the ER stress conditions. We also
PRIMARY OBJECTIVES:. I. To define the maximum tolerated dose (MTD) and describe the toxicities of wild-type reovirus (Reolysin) when given once a day for three days following two days of treatment with sargramostim (GM-CSF).. SECONDARY OBJECTIVES:. I. To assess the safety, tolerability and adverse events in the patient population.. II. To assess the median overall survival time in this patient population. III. To assess the median progression free survival time in this patient population.. TERTIARY OBJECTIVES:. I. To determine whether there is a correlation between antibody responsiveness to the virus and a positive tumor response to Reolysin in patients who receive the virus following treatment with GM-CSF.. II. To determine whether there is a correlation between an increased number of circulating monocytes and a positive tumor response to Reolysin in patients who receive the virus following treatment with GM-CSF.. III. To explore the possible predictive value of monocyte numbers in response to ...
SWISS-MODEL Template Library (SMTL) entry for 1rwk.1. Crystal structure of human caspase-1 in complex with 3-(2-mercapto-acetylamino)-4-oxo-pentanoic acid
A previous study showed evidence of ER stress in the liver and adipose tissue of insulin-resistant obese mice, including leptin-deficient ob/ob mice (Ozcan et al., 2004), and we found that macrophages from ob/ob mice are more susceptible to ER stress-induced apoptosis (Senokuchi et al., 2008). Therefore, we compared macrophages from WT and ob/ob mice for CHOP expression and IICR. We found that macrophages freshly harvested from ob/ob mice had elevated expression of Chop mRNA and showed a striking elevation of IICR compared with macrophages from WT mice (Fig. 5, b and c). Thus, macrophage IICR is elevated in an in vivo model of insulin resistance-induced ER stress.. In summary, our data provide evidence for a new pathway linking the CHOP branch of the UPR to calcium-induced apoptosis, a scenario which has been implicated in a wide range of disease processes (Kim et al., 2008). In this sense, the mechanism revealed herein may complement another calcium-mediated apoptosis process induced by the ...
1. WelchmanRLGordonCMayerRJ 2005 Ubiquitin and ubiquitin-like proteins as multifunctional signals. Nat Rev Mol Cell Biol 6 599 609. 2. HickeLSchubertHLHillCP 2005 Ubiquitin-binding domains. Nat Rev Mol Cell Biol 6 610 621. 3. ChenZJSunLJ 2009 Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell 33 275 286. 4. MukhopadhyayDRiezmanH 2007 Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 315 201 205. 5. LeeTVDingTChenZRajendranVScherrH 2008 The E1 ubiquitin-activating enzyme Uba1 in Drosophila controls apoptosis autonomously and tissue growth non-autonomously. Development 135 43 52. 6. DegterevAYuanJ 2008 Expansion and evolution of cell death programmes. Nat Rev Mol Cell Biol 9 378 390. 7. KumarS 2007 Caspase function in programmed cell death. Cell Death Differ 14 32 43. 8. BaoQShiY 2007 Apoptosome: a platform for the activation of initiator caspases. Cell Death Differ 14 56 65. 9. RiedlSJSalvesenGS 2007 The apoptosome: signalling platform of cell ...
CALGARY, October 24, 2007 PRNewswire-FirstCall - Oncolytics Biotech Inc. ( Oncolytics ) today announced that a poster presentation covering interim results from
Standard treatment for advanced malignant pleural mesothelioma (MPM) is a cisplatin/pemetrexed (MTA) regimen; however, this is confronted by drug resistance. Proteotoxic stress in the endoplasmic reticulum (ER) is a hallmark of cancer and some rely on this stress signalling in response to cytotoxic chemotherapeutics. We hypothesise that ER stress and the adaptive unfolded protein response (UPR) play a role in chemotherapy resistance of MPM. In vitro three-dimensional (3D) and ex vivo organotypic culture were used to enrich a chemotherapy-resistant population and recapitulate an in vivo MPM microenvironment, respectively. Markers of ER stress, the UPR and apoptosis were assessed at mRNA and protein levels. Cell viability was determined based on acid phosphatase activity. MPM cells with de novo and/or acquired chemotherapy resistance displayed low ER stress, which rendered the cells hypersensitive to agents that induce ER stress and alter the UPR. Bortezomib, an FDA-approved proteasome inhibitor,
In this paper, we demonstrate that in soybean cells CPA determines an ER stress, which in turn induces a PCD program involving a biphasic increase in [Ca2+]cyt, generation of H2O2, release of mitochondrial cytochrome c, activation of caspase-like proteases and chromatin condensation.. Accumulating evidence shows that besides its crucial role as an important Ca2+ store and in protein maturation, folding and transport, the ER is emerging as a central player in apoptosis (Rizzuto et al., 1998; Berridge, 2002). The data so far available comes mainly from mammalian cells, although the precise involvement of the ER in the apoptotic response has not yet been completely unraveled. In animal cells disturbance of ER functions have been shown to trigger apoptotic pathways involving a cross-talk between ER and mitochondria, which is regulated by Bcl-2 protein, and the activation of ER-resident caspase 12 as mediator of death signaling (Hacki et al., 2000; Nakagawa and Yuan, 2000; Nakagawa et al., 2000). In ...
ER stress-induced processing and nuclear translocation of GFP-ATF6. (a) Twenty-four hours after transfection with pCMVshort-EGFP-ATF6 (WT), 293T cells were left
Procaspase 8 and 10 are known as initiator caspases. These are inactive molecules, but when bought into close proximity with ... initiating the caspase cascade. The activated caspases can go on to cleave intracellular proteins such as inhibitor of caspase- ... Activated caspase 8 cleaves these kinases, inhibiting necroptosis. Since activation of caspase 8 requires FADD in order to ... "Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8". Journal of ...
Initiator caspases: responsible for the activation of effector caspases. These caspases are activated through oligomerization ... FLIPL's pseudo-caspase has two tandem DEDs that are very similar to the N-terminus of capase-8, but in which there is an ... Studying caspases is important since they don't only control apoptosis but also inhibit it, depending on the necessity of the ... This type of apoptosis depends on the pDED of the HIP-1, and it consists in the activation of caspase-3, an enzyme that is ...
There are two types of caspases: initiators and effectors. Initiator caspases cleave inactive forms of effector caspases. This ... This pathway controls the activation of caspase-9 by regulating the release of cytochrome c from the mitochondrial ... Caspases (cysteine-aspartic acid proteases) cleave at very specific amino acid residues. ... each leading to the activation of caspase-9. The nucleus and Golgi apparatus are other organelles that have damage sensors, ...
This pathway is made up of a series of proteins called initiator and executioner caspases. Initiator caspases help form an ... When activated, Fas turns on what is called a "caspase cascade". ... Executioner caspases go on to "digest" the cell from the inside ... apoptosis initiation factor that eventually activates executioner caspases (see figure 3). ...
Reduction of potassium ions promotes apoptosis and the synthesis of initiator caspase-8 and the effector caspase-3. A study ... that while caspase may play a role in apoptosis, it is specifically not as a result of caspase-3. It was reported in that study ... Caspase I is involved in the aforementioned cell membrane activity but not caspase-3. The sequence of events that leads to ... There are also differences in the initiation of mitochondrial (internal) and caspase-dependent (external) apoptosis for the UVC ...
... this initiator caspase can then activate effector caspases and trigger a cascade of events leading to apoptosis. The term ... In each case, caspase 9 activation leads to the activation of a full caspase cascade and subsequent cell death. It has been ... This functional apoptosome then can provide a platform activation of caspase 9. Caspase 9 exists as a zymogen in the cytosol ... In addition, several other molecules, most notably caspase-3, have been reported to co-purify with the apoptosome and caspase-3 ...
... response modifier a inhibition of initiator caspases results in covalent complex formation and dissociation of the caspase ... Caspase 8 initiates apoptosis by activating "executioner" caspases, numbered 3, 6, and 7. By inhibiting caspase 8, crmA ... The best characterized IAP is XIAP, which binds caspase-9, caspase-3 and caspase-7, thereby inhibiting their activation and ... Inhibition of caspase 8 also prevents cell death signals by ligation of a TNF super family member known as death receptors, ...
... initiator caspases, caspase 2,8,9,10,11,12, and effector caspases, caspase 3,6,7. The activation of initiator caspases requires ... caspase-8 and caspase-10. In some types of cells (type I), processed caspase-8 directly activates other members of the caspase ... Effector caspases are then activated by these active initiator caspases through proteolytic cleavage. The active effector ... The two pathways both activate initiator caspases, which then activate executioner caspases, which then kill the cell by ...
In caspase-3 the 'hook' and 'sinker' attach. Both the BIR2 and BIR3 have a groove that is predominately negatively charged. ... an apoptosis initiator. The three-dimensional structure of all BIR domains is constructed of two to three NH2-terminus α- ... This is done through the binding to caspases directly. Similar to the functionality of NAIP, the BIR3 domain of XIAP binds to ... This is unexpected because, in nerve growth factor withdrawal, caspase-3 and -9 are activated, causing cell death, which are ...
Once inside the target cell, granzyme B can cleave and activate initiator caspases 8 and 10, and executioner caspases 3 and 7 ... Caspase 7 is the most sensitive to granzyme B and caspases 3, 8, and 10 are only cleaved to intermediate fragments and need ... The caspase independent pathways of cell death are thought to have arisen to overcome viruses that can inhibit caspases and ... into a 50 kDa fragment and then into an additional 60 kDa indirectly through the caspases it activates. Granzyme B can degrade ...
... also does not bind to active caspase-8. Caspase-3 and -7 are effector proteases whereas caspase-8 is an initiator ... which recruits activator caspases like caspase-8 upon binding TNF at the cell surface. The activation of the initiator caspases ... The human IAPs, XIAP, c-IAPl, C-IAP2 have been shown to bind to caspase-3 and -7, which are the effector caspases in the ... Active caspase-3 and -7 coimmunoprecipitated with survivin. The inactive proforms of caspase-3 and -7 did not bind survivin. ...
... acting as an initiator caspase. Ced-3 gene is found downstream of ced-4 and positively regulates ced-3. It can also be ... caspase 9. Its name is derived from the term "cell death". Structurally, ced-3 has two protein domains: CARD domain (Caspase ... thus becoming a functional caspase. Ced-3 is an executioner caspase (cysteine-dependent aspartate-directed protease) that must ... The caspase domain is the main domain of the protein, where the cleavage activity of the protease takes place. The active ...
There are two types of caspases: initiators and effectors. Initiator caspases cleave inactive forms of effector caspases. This ... Pharmacological approaches involve inhibitors of caspase activity, and caspase inhibition might delay cell death in the ... This pathway controls the activation of caspase-9 by regulating the release of cytochrome c from the mitochondrial ... Caspases (cysteine-aspartic acid proteases) cleave at very specific amino acid residues. ...
... 2, Caspase 8, Caspase 9, Caspase 10) Executioner Caspases (Caspase 3, Caspase 6 and Caspase 7) Once initiator caspases ... Caspase-1, Caspase-4, Caspase-5 and Caspase-11 are considered 'Inflammatory Caspases'. Caspase-1 is key in activating pro- ... Initiator caspases auto-proteolytically cleave whereas Executioner caspases are cleaved by initiator caspases. This hierarchy ... Caspase-1, Caspase-4 and Caspase-5 in humans, and Caspase-1 and Caspase-11 in mice play important roles in inducing cell death ...
... is an initiator caspase, as are caspase-8 (EC, caspase-9 (EC and caspase-10 (EC ... Caspase-2 (EC, ICH-1, NEDD-2, caspase-2L, caspase-2S, neural precursor cell expressed developmentally down-regulated ... Li H, Bergeron L, Cryns V, Pasternack MS, Zhu H, Shi L, Greenberg A, Yuan J (August 1997). "Activation of caspase-2 in ... Mancini M, Machamer CE, Roy S, Nicholson DW, Thornberry NA, Casciola-Rosen LA, Rosen A (May 2000). "Caspase-2 is localized at ...
Gly Caspase-10 is an initiator caspase, as are caspase-2 (EC, caspase-8 (EC and caspase-9 (EC ... Shikama Y, Yamada M, Miyashita T (July 2003). "Caspase-8 and caspase-10 activate NF-kappaB through RIP, NIK and IKKalpha ... "Unique and overlapping substrate specificities of caspase-8 and caspase-10". Oncogene. 25 (1): 152-9. doi:10.1038/sj.onc. ... Caspase-10 (EC, FLICE2, Mch4, CASP-10, ICE-like apoptotic protease 4, apoptotic protease Mch-4, FAS-associated death ...
... is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic ... Once activated, caspase-9 goes on to cleave caspase-3, -6, and -7, initiating the caspase cascade as they cleave several other ... Active caspase-9 works as an initiating caspase by cleaving, thus activating downstream executioner caspases, initiating ... Different protein isoforms of caspase-9 are produced due to alternative splicing. Similar to other caspases, caspase-9 has ...
Wang, J; Chun H J; Wong W; Spencer D M; Lenardo M J (November 2001). "Caspase-10 is an initiator caspase in death receptor ... Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive ... Caspase 10 has been shown to interact with FADD, CFLAR, Caspase 8, Fas receptor, RYBP, TNFRSF1A and TNFRSF10B. The Proteolysis ... This protein cleaves and activates caspases 3 and 7, and the protein itself is processed by caspase 8. Mutations in this gene ...
... has a similar amino acid sequence to initiator caspases, including caspase 1, caspase 4, caspase 5, and caspase 9. It ... Overall, caspase 2 appears to be a very versatile caspase with multiple functions beyond cell death induction. Caspase 2 has ... Within this family, caspase 2 is part of the Ich-1 subfamily. It is one of the most conserved caspases in different species of ... Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive ...
It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an ... Instead, it is thought to inhibit Caspase-1 activation by interfering with the interaction of Caspase-1 with other important ... and a caspase, in this case Caspase-1. In some cases, where the signaling proteins contain their own CARDs, like in NLRP1 and ... Caspase-1 is produced as a zymogen that can then be cleaved into 20 kDa (p20) and 10 kDa (p10) subunits that become part of the ...
As an executioner caspase, the caspase-3 zymogen has virtually no activity until it is cleaved by an initiator caspase after ... Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the CASP3 gene. CASP3 orthologs ... XIAP binds and inhibits initiator caspase-9, which is directly involved in the activation of executioner caspase-3. During the ... Caspase substrate specificity has been widely used in caspase based inhibitor and drug design. Caspase-3, in particular, (also ...
Executioner Caspases (Caspase 3, Caspase 6 and Caspase 7). Once initiator caspases are activated, they produce a chain reaction ... Initiator caspases auto-proteolytically cleave whereas Executioner caspases are cleaved by initiator caspases. This hierarchy ... Caspase-1, Caspase-4, Caspase-5 and Caspase-11 are considered 'Inflammatory Caspases'.[7] ... Caspase-1, Caspase-4 and Caspase-5 in humans, and Caspase-1 and Caspase-11 in mice play important roles in inducing cell death ...
This protein is a flavoprotein that functions as an NAD(P)H-dependent oxidoreductase and induces caspase- and p53-independent ... Sequence analysis reveals that the AIFM2 gene promoter contains a consensus transcription initiator sequence instead of a TATA ... induces caspase-independent apoptosis". The Journal of Biological Chemistry. 277 (28): 25617-23. doi:10.1074/jbc.M202285200. ...
"Glucocorticoid modulatory element-binding protein 1 binds to initiator procaspases and inhibits ischemia-induced apoptosis and ... "Regulation of procaspase-2 by glucocorticoid modulatory element-binding protein 1 through the interaction with caspase ...
... caspase-dependent cell death, p53 dependent apoptosis, cell proliferation and autophagy as well as hypoxia, although there are ... after the initiator methionine (iMet) has been cleaved by methionine aminopeptidases (MetAP). Furthermore, post-translational ... "A genome-wide RNAi screen reveals multiple regulators of caspase activation". The Journal of Cell Biology. 179 (4): 619-26. doi ...
In contrast with IL-1, processing by caspases, like caspase-1, results in IL-33 inactivation. IL-33 is a dual function cytokine ... IL-1α also stimulates transcription and secretion of IL-1β from monocytes, so the initiator of immune responses is likely IL-1α ... the IL-1β precursor has to be cleaved by a cysteine protease called caspase-1. Caspase-1 needs to be activated by a formation ... IL-18 is also synthesized as a precursor which is cleaved by caspase-1. There are indications that IL-1, not least IL-1beta, is ...
In addition to the induction of caspase-dependent apoptosis through the mitochondrial pathway, bafilomycin also causes ... which is an initiator of apoptosis. Bafilomycin has also been shown to induce both inhibition of autophagy and subsequent ...
... the most notable ones being caspases 2, 3, and 9. Cell death is not prevented by caspase inhibitors, or by BCL-2 or p53 ... HAMLET cells and cells under conditions of amino acid starvation (a known initiator of macroautophagy) showed similar ... physical damage to the mitochondrial membranes and assays have found cytochrome c release and activation of the caspase cascade ... mutagenesis, indicating that the traditional apoptotic caspase cascade is not the ultimate cause of cell death. Another target ...
May 2012). "Influenza induces endoplasmic reticulum stress, caspase-12-dependent apoptosis, and c-Jun N-terminal kinase- ... cytosolic domain causes translational attenuation by directly phosphorylating the α subunit of the regulating initiator of the ... at which point human procaspase 4 is believed to cause apoptosis by activating downstream caspases. Although PERK is recognised ... cytochrome c release and caspase 3 activation. Diseases Diseases amenable to UPR inhibition include Creutzfeldt-Jakob disease, ...
Executioner Caspases (Caspase 3, Caspase 6 and Caspase 7). Once initiator caspases are activated, they produce a chain reaction ... Initiator caspases auto-proteolytically cleave whereas Executioner caspases are cleaved by initiator caspases. This hierarchy ... Caspase-1, Caspase-4, Caspase-5 and Caspase-11 are considered 'Inflammatory Caspases'.[7] ... Caspase-1, Caspase-4 and Caspase-5 in humans, and Caspase-1 and Caspase-11 in mice play important roles in inducing cell death ...
... the most notable ones being caspases 2, 3, and 9.[7] Cell death is not prevented by caspase inhibitors, or by BCL-2 or p53 ... HAMLET cells and cells under conditions of amino acid starvation (a known initiator of macroautophagy) showed similar ... physical damage to the mitochondrial membranes and assays have found cytochrome c release and activation of the caspase cascade ... mutagenesis, indicating that the traditional apoptotic caspase cascade is not the ultimate cause of cell death. ...
... initiator caspases, caspase 2,8,9,10,11,12, and effector caspases, caspase 3,6,7. The activation of initiator caspases requires ... caspase-8 and caspase-10. In some types of cells (type I), processed caspase-8 directly activates other members of the caspase ... Effector caspases are then activated by these active initiator caspases through proteolytic cleavage. The active effector ... The two pathways both activate initiator caspases, which then activate executioner caspases, which then kill the cell by ...
The radicals serve as initiator of radical polymerization, which surrounds the eggs with a protective layer of polymer.[40] ... "Oxidative Stress-Induced Caspases are Regulated in Human Myeloid HL-60 Cells by Calcium Signal". Current Signal Transduction ...
Wang KK (Jan 2000). "Calpain and caspase: can you tell the difference?". Trends in Neurosciences. 23 (1): 20-26. doi:10.1016/ ... actin is capable of acting as a transcription initiator when it reacts with a type of nuclear myosin that interacts with RNA ... Villa PG, Henzel WJ, Sensenbrenner M, Henderson CE, Pettmann B (Mar 1998). "Calpain inhibitors, but not caspase inhibitors, ...
In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin- ... the functional abnormalities and/or the degeneration of which are believed to be the initiators and major pathologies of macula ...
But in contrast, the caspase-2, which is acetylated by NatA, can interact with the adaptor protein RIP associated Ich-1/Ced-3 ... NatA acetylates Ser, Ala-, Gly-, Thr-, Val- and Cys N-termini after the initiator methionine is removed by methionine amino- ... homologous protein with a death domain (RAIDD). This could activate caspase-2 and induce cell apoptosis. Ribosome proteins play ...
... in the assembly of the ULK1-Beclin 1-ATG16L1 initiator complex on TRIM16 during endomembrane damage. Galectin-1 has been shown ... novel inducer of T cell apoptosis with distinct profile of caspase activation". Journal of Immunology. 173 (6): 3825-37. doi: ...
Once activated, the initiator caspases can activate other caspases such as the EFFECTOR CASPASES. ... A subtype of caspases that contain long pro-domain regions that regulate the activation of the enzyme. The pro-domain regions ... the activities of the effecter caspase, caspase-3, and the initiator caspases, caspase-8 and caspase-9, which are ... the activities of effecter caspases - caspase-3/7 - and initiator caspases - caspase-8 and caspase-9 - that are representative ...
Cytotoxic stress, such as that caused by cancer therapies, leads to activation of caspase-2, which acts as a direct effector of ... The cell death protease caspase-2 has recently been recognized as the most apical caspase in the apoptotic cascade ignited ... Crystal structure of caspase-2, apical initiator of the intrinsic apoptotic pathway J Biol Chem. 2003 Oct 24;278(43):42441-7. ... These features form the basis of caspase-2 specificity and allow the design of caspase-2-directed ligands for medical and ...
... also has been shown to be an initiator caspase. However, the timing or activation sequence of these initiator caspases, which ... Caspase-2 is an initiating caspase required for stress-induced apoptosis in various human cancer cells. Activation of caspase-9 ... These data suggest parallel activation of initiator caspase-2 and caspase-9 in cisplatin-induced cell death. ... Simultaneous imaging of two initiator caspases during cisplatin-induced HeLa apoptosis Author(s): Jun Chu; Liang Wang; Qingming ...
Lymantria dispar Multiple Nucleopolyhedrovirus Precludes Apoptosis by Preventing Proteolytic Processing of Initiator Caspase ... Lymantria dispar Multiple Nucleopolyhedrovirus Precludes Apoptosis by Preventing Proteolytic Processing of Initiator Caspase ... Lymantria dispar Multiple Nucleopolyhedrovirus Precludes Apoptosis by Preventing Proteolytic Processing of Initiator Caspase ... Lymantria dispar Multiple Nucleopolyhedrovirus Precludes Apoptosis by Preventing Proteolytic Processing of Initiator Caspase ...
Usually, IAPs bind to and inhibit activated, i.e. processed caspases, including CASPASE-3, CASPASE-7 and CASPASE-9 as well as ... the initiator caspase DRONC and the effector caspases DrICE and DCP-1 are essential for apoptosis [11]-[18]. Like human CASPASE ... caspases [7]. The long prodomains of initiator caspases harbor regulatory motifs such as the caspase activation and recruitment ... is characterized by increased caspase activity [49]. Intriguingly, the protein levels of CASPASE-3, CASPASE-7 and CASPASE-9 did ...
Within their long prodomains, caspases-2, -9 and -12 contain a caspase activation and recruitment domain while caspases-8 and - ... Mammalian initiator apoptotic caspases Academic Article * View record in Web of Science ® ... regulation and signaling mechanisms differ between initiator apoptotic caspases. Defects in expression or activity of these ... Caspases are a conserved family of cysteine proteases. They play diverse roles in inflammatory responses and apoptotic pathways ...
Executioner caspases have only rarely been found mutated or silenced, and also initiator caspases are only affected in ... Loss of the initiator caspase of the intrinsic apoptotic pathway, caspase-9, however, did not promote cellular transformation. ... There is experimental evidence from transgenic mice that certain initiator caspases, such as caspase-8 and -2, might act as ... Apoptosis is ultimately carried out by the sequential activation of initiator and executioner caspases, which constitute a ...
... with murine caspase-12 and human caspase-4 acting as the initiator caspases. Once activated, caspase-12 or -4 can, in turn, ... caspase-12 activation occurred upstream of other initiator/executioner caspases, and inhibition/deletion of caspase-12 ... Regulation of ER-associated initiator caspases by BCL-2 family members. Studies using BAX/BAK DKO cells have shown that caspase ... Caspase-12 was initially identified as an ER-localized caspase selectively activated by ER stress, and deletion of caspase-12 ...
Executioner Caspases (Caspase 3, Caspase 6 and Caspase 7). Once initiator caspases are activated, they produce a chain reaction ... Initiator caspases auto-proteolytically cleave whereas Executioner caspases are cleaved by initiator caspases. This hierarchy ... Caspase-1, Caspase-4, Caspase-5 and Caspase-11 are considered Inflammatory Caspases.[7] ... Caspase-1, Caspase-4 and Caspase-5 in humans, and Caspase-1 and Caspase-11 in mice play important roles in inducing cell death ...
Caspase-10 is an initiator caspase in death receptor signaling. Proc Natl Acad Sci USA 2001;98:13884-8. ... Expression of Effector Caspases.. Caspase-3 has been identified as the major effector caspase in most mammalian cells (86 , 87) ... caspases-8, -9, and -10 are involved in the initiation steps that result in caspase activation; and the exact roles of caspases ... Expression of Initiator Caspases.. In additional experiments, expression of the same polypeptides was examined in the 60 cell ...
Procaspase 8 and 10 are known as initiator caspases. These are inactive molecules, but when bought into close proximity with ... initiating the caspase cascade. The activated caspases can go on to cleave intracellular proteins such as inhibitor of caspase- ... Activated caspase 8 cleaves these kinases, inhibiting necroptosis. Since activation of caspase 8 requires FADD in order to ... "Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8". Journal of ...
Initiator caspases: responsible for the activation of effector caspases. These caspases are activated through oligomerization ... FLIPLs pseudo-caspase has two tandem DEDs that are very similar to the N-terminus of capase-8, but in which there is an ... Studying caspases is important since they dont only control apoptosis but also inhibit it, depending on the necessity of the ... This type of apoptosis depends on the pDED of the HIP-1, and it consists in the activation of caspase-3, an enzyme that is ...
In return of caspase-8, caspase-9 is the hallmark of intrinsic pathway. Once the initiator caspases have been activated, they ... 2.2.1. Caspases are central initiators and executioners of apoptosis. The term caspase is derived from cysteine-dependent ... The proapoptotic caspases can be divided into the group of initiator caspases including procaspases-2, -8, -9, and -10, and ... with caspase-11 and caspase-12 only identified in the mouse [30, 31]. According to a unified nomenclature, the caspases are ...
... caspases can be divided into initiator and effector caspases. Initiator caspases, such as caspase-8 or -9, exert regulatory ... α-Toxin activates the initiator caspases 8 and 9. Caspase-3 activation can be achieved either by caspase-8, the most proximal ... caspase in death receptor signaling, or by caspase-9, the initiator caspase of the mitochondrial pathway. To elucidate which of ... the two major initiator caspases. The activation of caspase-8 might be indicative for the involvement of CD95 as suggested ...
Group I: inflammatory caspases; group II: apoptosis initiator caspases; group III: apoptosis effector caspases. The CARD, the ... caspase-2 (20), caspase-3 (21-23), caspase-7 (24-26), caspase-8 (27), and caspase-9 (28). The overall architecture of all ... The caspases with large prodomains are referred to as inflammatory caspases (group I) and initiator of apoptosis caspases ( ... The effector caspases are activated by initiator or apical caspases. However, one central question of apoptosis is how ...
Specific adaptors regulate the activation of initiator caspases; for example, FADD and Apaf-1 engage caspases 8 and 9, ... Caspase-1 activation was not compromised by loss of RIP2. These data show that whereas ASC is key to caspase-1 activation ... Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf.. Mariathasan S1, Newton K, Monack DM, Vucic D, ... Furthermore, activation of caspase-1 in response to an intracellular pathogen (Salmonella typhimurium) was abrogated severely ...
... caspase-9, and caspase-10, and the effector caspases, consisting of caspase-3, caspase-6, and caspase-7. An initiator caspase ... The initiator caspases, however, are autoactivated. Since the activation of an initiator caspase in cells inevitably triggers a ... Caspases involved in apoptosis are generally divided into two categories: the initiator caspases, which include caspase-2, ... In the death receptor pathway, caspase-8 is the key initiator caspase. Death receptors are members of the tumor necrosis factor ...
Biochemical analyses showed that T lymphocytes with the deletion variant had lower caspase-8 activity and activation-induced ... Caspases are important in the life and death of immune cells and therefore influence immune surveillance of malignancies. We ... Ho, P.K. & Hawkins, C.J. Mammalian initiator apoptotic caspases. FEBS J. 272, 5436-5453 (2005). ... Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade. Blood 99, ...
Procaspase-8, the zymogen type of the apoptosis-initiator caspase-8, undergoes phosphorylation following. February 7, 2018. ... Outcomes Caspase-8 interacts with CrkL SH2 domains We observed the de novo phosphorylation of many protein, in caspase-8 ... Procaspase-8, the zymogen type of the apoptosis-initiator caspase-8, undergoes phosphorylation following integrin-mediated cell ... To determine whether the phosphoprotein may end up being component of a complicated linked with the caspase, caspase-8 ...
Activation of Initiator Caspases. George L. McLendon, Duke University, USA Short Talk: Novel Targets for Apoptosis. ... Role of Caspase 8 in Proliferation and Survival. Francesco Cecconi, University of Rome Tor Vergata, Italy The Centrality of the ... Discovery of an Orphan Allosteric Site in Caspase by Tethering. Leigh Zawel, Merck Research Labs, USA Development of Smac ... A Re-Evaluation of the Induced Proximity Model for Caspase Activation. * John C. Reed, F. Hoffmann-La Roche AG, Switzerland ...
... a caspase can cleave and activate other caspases; thus initiator caspases can activate effector caspases resulting in a great ... activated by stress in the ER (excessive unfolded proteins) then activates caspase 9 and the rest of the caspase cascade ... ligands, receptors, caspase activation mediate this route; involves signaling molecules of the Tumor Necrosis Factor family, ... ligands, receptors, caspase activation mediate this route; involves signaling molecules of the Tumor Necrosis Factor family, ...
A hierarchy of caspase activation exists whereby initiator caspases become activated to cleave and activate effector caspases. ... caspases (2, 8, 9 and 10) is much longer than that of effector caspases 3, 6 and 7. For the initiator caspases, binding to ... Once active, initiator caspases proteolytically cleave effector caspases at distinct aspartate residues, to release the ... Keywords: initiator caspase; effector caspase; membrane blebbing; nuclear disintegration; cellular condensation; apoptotic ...
Specific adaptors regulate the activation of initiator caspases; for example, FADD and Apaf-1 engage caspases 8 and 9, ... Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1 NATURE Broz, P., Ruby, T., Belhocine, K ... Caspase-1 activation was not compromised by loss of RIP2. These data show that whereas ASC is key to caspase-1 activation ... Both ASC and caspase-1 play a critical role in host defense against Francisella infection in vivo. Activation of caspase-1 ...
Novel initiator caspase reporters uncover unknown features of caspase-activating cells. Luis Alberto Baena-Lopez, Lewis ...
Novel initiator caspase reporters uncover unknown features of caspase-activating cells. Luis Alberto Baena-Lopez, Lewis ...
Activation of initiator caspases. The available evidence indicates that activation of initiator caspases requires binding to ... Different initiator caspases mediate distinct sets of signals. For example, caspase-8 is associated with apoptosis involving ... A) Caspases have been found in organisms ranging fromC. elegans to humans. The 13 identified mammalian caspases (named caspase- ... 3): a proapoptotic signal culminates in activation of an initiator caspase which, in turn, activates effector caspases, ...
Chen M, Wang J (2002) Initiator caspases in apoptosis signaling pathways. Apoptosis 7:313-319CrossRefPubMedGoogle Scholar ...
... or as an initiator (Thornberry and Lazebnik, 1998). Our data would support a role for caspase-2 as an initiator, which then ... The activation of caspase-3 may be occurring in parallel with that of caspase-2, or caspase-2 may be activating caspase-3. ... a substrate for caspases related to caspase-3. This peptide is not cleaved by caspase-2 and minimally cleaved by caspase-1 ... Caspase-2 has been classified as either an effector, together with caspase-3 and caspase-7 (Thornberry et al., 1997), ...
First, caspase-1 induces the activation and secretion of the two prominent pro-inflammatory cytokines, interleukin-1β (IL-1β) ... Inflammatory caspases play a central role in innate immunity by responding to cytosolic signals and initiating a twofold ... Caspases, Initiator * Caspase 1 Grant support * R01 AI097518/AI/NIAID NIH HHS/United States ... Second, either caspase-1 or caspase-11 can trigger a form of lytic, programmed cell death called pyroptosis. Pyroptosis ...
Caspase-10 is an initiator caspase in death receptor signaling Jin Wang, Hyung J. Chun, Wilson Wong, David M. Spencer, and ...
  • Caspases are a conserved family of cysteine proteases. (edu.au)
  • Third, pathways upstream of caspase activation might be disrupted in tumor cells. (mdpi.com)
  • Based on their structure and order in cell death pathways, caspases can be divided into initiator and effector caspases. (rupress.org)
  • Notably, cell death triggered by stimuli that engage caspase-1 was ablated in macrophages lacking either ASC or Ipaf, suggesting a coupling between the inflammatory and cell death pathways. (nih.gov)
  • Activation of caspases through intrinsic and extrinsic death pathways. (els.net)
  • Depending on individual (patho-) physiological circumstances, cell-type and involved receptor-ligand system, cellular responses range from activation of pro-inflammatory and potentially pro-tumoural pathways such as nuclear factor κB (NFκB), to caspase-dependent and -independent mechanisms of cell death induction. (mdpi.com)
  • This report gives an insight into Apoptosis Mechanism, by Molecular Pathways - Caspase Activators and Inhibitors, Protease/Proteasome Inhibitors, Bcl-2 Modulators and p53 Modulators. (researchimpact.com)
  • Both pathways finally end up in the level of activation of caspases for cell death. (thefreelibrary.com)
  • The model integrates current information concerning the signaling network downstream of Fas activation, through both type I and type II pathways, until activation of caspase-3. (jimmunol.org)
  • For both pathways, caspases, a family of cysteine proteases, are crucial for both the initiation and execution of apoptosis. (jimmunol.org)
  • The pathways diverge after activation of initiator caspases (e.g., caspase-8 and caspase-10) and converge at the end by activating executor caspases (e.g., caspase-3). (jimmunol.org)
  • The specific mechanisms behind apoptosis such as the caspase cascade prove difficult to examine in vivo because many pathways become interrelated or codependent. (aacrjournals.org)
  • We are investigating the regulation of caspase activation in various apoptosis pathways. (upenn.edu)
  • Taken together, these results show that restoration of TFPI-2 activates both intrinsic and extrinsic caspase-mediated, proapoptotic signaling pathways and induces apoptosis in U-251 cells. (aacrjournals.org)
  • Caspases (cysteinyl aspartate proteases) are involved in the signaling pathways of apoptosis, necrosis and inflammation. (genecards.org)
  • Among its related pathways are Apoptosis and survival Caspase cascade and CDK-mediated phosphorylation and removal of Cdc6 . (genecards.org)
  • Apoptosis occurs via two pathways: the extrinsic (death receptor) pathway, initiated by activation of members of the death receptor superfamily (Fas and tumor necrosis factor receptor 1 [TNFR1]), leading to caspase 8 activation ( 61 ), and the intrinsic (mitochondrial) pathway, resulting in the mitochondrial release of cytochrome c and caspase 9 activation ( 80 ). (asm.org)
  • These two pathways converge upon the activation of caspase 3 ( 33 ). (asm.org)
  • Tamoxifen-induced toxicity was shown to occur through both caspase-dependent and caspase-independent cell death pathways. (arvojournals.org)
  • Simultaneous inhibition of caspase-dependent and caspase-independent cell death pathways is required to protect cells from tamoxifen. (arvojournals.org)
  • Taken together, our results indicate that ALSL-induced apoptosis of A375 cells is mediated by both mitochondrial caspase-dependent and -independent pathways and it involves ROS and JNK activation in the mitogen-activated protein kinase cascade. (springer.com)
  • Chen M, Wang J (2002) Initiator caspases in apoptosis signaling pathways. (springer.com)
  • Budihardjo I, Oliver H, Lutter M, Luo X, Wang X (1999) Biochemical pathways of caspase activation during apoptosis. (springer.com)
  • For providing a better understanding of the mechanism of action of mTOR inhibitors and caspase/apoptosis inhibitors, the mTOR and caspase signaling pathways in normal and PKD kidneys are reviewed. (asnjournals.org)
  • Therefore it remains important to gain a detailed understanding of the mechanisms behind native caspase-9 regulatory pathways and harness these mechanisms for therapeutic purposes. (umass.edu)
  • It cleaves and activates caspase-3, -4, -6, -7, -8 and -9, is recruited to Fas- and TNFR-1 receptors in a FADD-dependent manner, and may participate in the granzyme B apoptotic pathways. (thefreedictionary.com)
  • Induction of stress signalling pathways JNK/SAPK causes release of cytochrome c from mitochondria and activation of apaf-1 (apoptosome), which in turn cleaves the pro-enzyme of caspase-9 into the active form. (creativebiomart.net)
  • Parasitic infection dose dependently diminished cleavage of caspase 8, the BH3-only protein Bid, and the downstream caspases 9 and 3. (curehunter.com)
  • Activation of caspases occurs through dimerization and proteolytic cleavage, separating the large and small subunits. (prolekare.cz)
  • Activation involves dimerization and often oligomerisation of pro-caspases, followed by cleavage into a small subunit and large subunit. (wikipedia.org)
  • Cleavage of the procaspase at the specific Asp-X bonds leads to the formation of the mature caspase, which comprises the heterotetramer p20 2 -p10 2 , and the release of the prodomain. (jci.org)
  • Although the preferred tetrapeptide motif differs among caspases, the preferred specificity of cleavage for caspases can be described as X-Glu-X-Asp [ 7 ]. (hindawi.com)
  • Caspase‐mediated cleavage of target proteins may produce stable functional effector fragments or unstable fragments that are quickly degraded. (els.net)
  • For the initiator caspases, binding to adaptor proteins results in the cleavage of the prodomain and subsequent rearrangement of the large and small subunits to produce a catalytically active heterodimer. (els.net)
  • These caspases can either directly activate caspase 3 or signal through the mitochondria via a Bid‐dependent cleavage event. (els.net)
  • Functional outcomes of caspase‐mediated cleavage. (els.net)
  • Following cleavage of a target protein by effector caspases, there are several probable functional consequences. (els.net)
  • a) Caspase‐mediated cleavage of intracellular proteins may result in the production of stable, functionally active effector fragments. (els.net)
  • These effector fragments may become newly active (as in the case of caspase‐mediated cleavage of ROCK1) or may act to inhibit normal protein function (e.g. caspase‐mediated cleavage of IKB renders the protein resistant to proteosomal degradation and thus allows for sustained inhibition of NFκB, see text for details). (els.net)
  • Caspase 3 activity was determined by assaying the cleavage of Ac-DEVD- p NA. (pnas.org)
  • Background: Caspase-3 (CPP-32, Apoptain, Yama, SCA-1) is a critical executioner of apoptosis, as it is either partially or totally responsible for the proteolytic cleavage of many key proteins, such as the nuclear enzyme poly (ADP-ribose) polymerase (PARP) (1). (cellsignal.com)
  • Cleavage of caspase-3 requires the aspartic acid residue at the P1 position (2). (cellsignal.com)
  • Caspase-3 Control Cell Extracts (Jurkat Untreated): Untreated Jurkat cells are lysed in Chaps cell extract buffer and a cytoplasmic fraction is generated to serve as a negative control for caspase cleavage. (cellsignal.com)
  • Extracts are treated with cytochrome c in vitro to generate a positive control for caspase cleavage. (cellsignal.com)
  • Etoposide treatment induces proteolytic cleavage of various apoptosis-related proteins including caspases, IAP, and PARP. (cellsignal.com)
  • Catalytically active Yersinia outer protein P induces cleavage of RIP and caspase-8 at the level of the DISC independently of death receptors in dendritic cells. (nih.gov)
  • Cleavage of caspase-8 and its preferred substrate, Bid, preceded processing of caspases-7 and -9, indicating that caspase-8 is the apical initiator caspase in TRAIL-induced apoptosis. (rupress.org)
  • These inclusions, which were also induced in untransfected cells, contained cytokeratins 8, 18, and 19, together with both a phosphorylated form and a caspase-cleavage fragment of cytokeratin 18. (rupress.org)
  • We propose that effector caspase-mediated cleavage of cytokeratins, resulting in disassembly of the cytoskeleton and formation of cytoplasmic inclusions, may be a characteristic feature of epithelial cell apoptosis. (rupress.org)
  • We report here that P49 and P35 use similar mechanisms for stoichiometric inhibition that require caspase cleavage of their reactive site loops (RSL) and chemical contributions of a conserved N-terminal cysteine to stabilize the resulting inhibitory complex. (pubmedcentralcanada.ca)
  • Caspase-mediated proteolysis promotes cellular disassembly that includes chromatin condensation, nuclear DNA cleavage, membrane blebbing, and cell fragmentation. (pubmedcentralcanada.ca)
  • Subsequently, the effector caspases are activated by initiator caspase-mediated cleavage of their inactive zymogen (procaspase) form. (pubmedcentralcanada.ca)
  • The retention of Spi-2 proteins' caspase-8 specificity during chordopoxvirus evolution, despite this function being readily lost through cleavage site mutagenesis, suggests that caspase-8 inhibition is crucial for poxviral pathogenesis and spread. (portlandpress.com)
  • Caspase-3 is the key executioner in this apoptotic pathway, responsible totally or critically in the proteolytic cleavage of cellular and nuclear proteins. (clinicaltrials.gov)
  • In this study, using the human T-lymphoma cell line, Jurkat cells, we investigated the apoptotic signal transduction mediated by FTY720, in particular comparing its role on the cleavage of caspases, with that mediated by etoposide or anti-Fas antibody. (aspetjournals.org)
  • Pretreatment with a broad caspase inhibitor [benzyloxycarbonyl-Val-Ala-Asp-(Ome) fluoromethyl ketone] markedly decreased the incidence of apoptotic cells induced by FTY720, etoposide, and anti-Fas antibody, through the abrogation of cleavage of Bid, poly(ADP-ribose) polymerase, and caspases 3, 8, and 9. (aspetjournals.org)
  • All caspases are synthesized as proenzymes and activated by cleavage at specific aspartate residues. (aspetjournals.org)
  • Caspases belong to a class of specific Cys proteases that show a high degree of specificity with an absolute requirement for cleavage adjacent an Asp residue and a recognition sequence of at least four amino acids N-terminal to this cleavage site. (plantphysiol.org)
  • Cleavage of a caspase molecule yields a large (α) subunit and a small (β) subunit that form the enzymatically active heterodimer. (plantphysiol.org)
  • The pX-dependent expression of Fas/FasL and TNFR1/TNF-α mediates caspase 8 activation, resulting in Bid cleavage. (asm.org)
  • Cytochrome c induces the heptamerization of the cytosolic protein Apaf‐1, which binds procaspase‐9 to form the active apoptosome complex for cleavage of effector caspases, whereas SMAC and HtrA2 act as inhibitors of IAPs. (els.net)
  • Caspases have a precursor form composed of a prodomain, and large and small catalytic subunit, and are activated through a cleavage adjacent to an aspartate to liberate units and allow formation of an a2b2 tetramer. (novusbio.com)
  • Intermediate caspase-9 cleavage forms may also be seen at ~21 kDa. (novusbio.com)
  • The caspase-10 was dispensable for enhancement of cisplatin/LA-12 and TRAIL combination-induced cell death and stimulation of Bid cleavage. (bireme.br)
  • Apoptosis in THP-1 cells induced by Z-LLL-CHO involved a cytochrome c -dependent pathway, which included the release of mitochondrial cytochrome c , activation of caspase-9 and -3, and cleavage of Bcl-2 into a shortened 22-kDa fragment. (aacrjournals.org)
  • Likewise, differentiated THP-1 cells were refractory to Z-LLL-CHO-induced cytochrome c release, caspase activation, and Bcl-2 cleavage. (aacrjournals.org)
  • Bilateral ballistic closed globe blunt ocular trauma was induced in female Lister-hooded rats and caspase-2 cleavage and localization assessed by Western blotting and immunohistochemistry. (arvojournals.org)
  • The initiator pro-caspases are activated exclusively by homodimerization in specific multi-protein activation platforms such as apoptosome, DISC, and PIDDosome [7].The mitochondrial pathway by which GzmB induces cell death is through the cleavage of the BH3-only protein Bid into a truncated form, tBid, which then translocates to the mitochondrion and disrupts mitochondrial membrane integrity through interactions with the pro-apoptotic proteins BAX and/or BAK. (thermofisher.com)
  • Here, we demonstrate that cleavage of the intersubunit linker of c-FLIP(L) by procaspase-8 potentiates the activation process by enhancing heterodimerization between the two proteins and vastly improving the proteolytic activity of unprocessed caspase-(C)8. (rcsb.org)
  • By cleaving critical proteins, caspases lead to the changes that characterize apoptosis both morphologically and biochemically, such as chromatin condensation, loss of cell adhesion, cell shrinkage, membrane blebbing, DNA fragmentation, and finally formation of apoptotic bodies, which stimulate their own engulfment by phagocytes. (mdpi.com)
  • Tumour growth can occur by a combination of factors, including a mutation in a cell cycle gene which removes the restraints on cell growth, combined with mutations in apoptopic proteins such as Caspases that would respond by inducing cell death in abnormally growing cells. (wikipedia.org)
  • The activated caspases can go on to cleave intracellular proteins such as inhibitor of caspase-activated DNase (ICAD), which ultimately leads to apoptosis of the cell. (wikipedia.org)
  • The DED domain is found in inactive procaspases (cysteine proteases) and proteins that regulate caspase activation in the apoptosis cascade such as FAS-associating death domain-containing protein (FADD). (wikipedia.org)
  • The presence of amino acids that determine the solubility and aggregation to DED allowed to identify DED's in different proteins, such as caspase-8 and MC159. (wikipedia.org)
  • These homologous endopeptidases belong to the large family of proteins called caspases (cysteine-dependent aspartate-specific protease). (hindawi.com)
  • The proteins that execute the apoptotic programme are a group of proteases termed caspases (cysteine‐dependent aspartate‐specific protease). (els.net)
  • Substrates targeted by caspases during the apoptotic programme include proteins involved in maintaining various aspects of cytoskeletal and organelle architecture as well as proteins that function in signalling networks critical for cell function. (els.net)
  • Apoptotic caspases are cysteine proteases that become activated in response to diverse extracellular and intracellular stimuli and subsequently carry out the cell death programme by systematically cleaving intracellular proteins. (els.net)
  • Once active, caspase 9 functions to proteolytically cleave and activate the effector caspases 3 and 7, which then go on to cleave numerous intracellular proteins to dismantle the cell. (els.net)
  • Caspase is a family of cysteine proteases, with specific cysteine residue that cleaves proteins after the aspartic acid residue, a specificity which is not normal among proteases to produce the active mature caspases [5]. (thefreelibrary.com)
  • This caspase-8 initiates other downstream proteins including procaspase-3 in two ways: the first is a complex pathway, wherein caspase8 cleaves Bcl-2 interacting protein named Bid and also releases cytochrome-c. (thefreelibrary.com)
  • In the family, Caspase-3 in its inactive zymogens, pro-caspase-3 is a remarkable protein as the enzyme shows a large substrate diversity, as a variety of proteins have been cleaved in cell maintenance. (thefreelibrary.com)
  • As the most understood of all cell death forms, apoptosis can be defined generally as a pathway involving the sequential proteolytic activation of Cys proteins called caspases, which in turn signal apoptotic machinery, most notably endonucleases. (aacrjournals.org)
  • Once activated, these caspases cleave and activate downstream effector caspases (including 3, 6 and 7), which in turn cleave cytoskeletal and nuclear proteins like PARP, α-fodrin, DFF and lamin A, and induce apoptosis. (cellsignal.com)
  • The NH 2 -terminal prodomains of initiator procaspases that facilitate the interaction between procaspases and their adaptor proteins are replaced by a derivative of FKBP called Fv. (sciencemag.org)
  • Upon apoptotic signaling, initiator caspases are autoactivated through interactions of their N-terminal prodomain with specific adaptor proteins ( 1 , 31 , 35 , 42 ). (pubmedcentralcanada.ca)
  • Biochemical analysis demonstrate that HCV proteins bring about the activation of initiator and effector caspases followed by severe apoptosis and mitochondria dysfunction, hallmarks of HCV cell injury. (biomedcentral.com)
  • Spi-2 proteins like CrmA potently inhibit caspases-1, -4 and -5, which produce proinflammatory cytokines, and caspase-8, which facilitates cytotoxic lymphocyte-mediated target cell death. (portlandpress.com)
  • These effector caspases then cleave various proteins such as those present in cytoskeletons and nucleus like lamin A, alpha-fodrin and poly (ADP-ribose) polymerase, leading to apoptosis. (clinicaltrials.gov)
  • In general, apoptotic cell death involves a sequence of caspase activation events in which initiator caspases activate downstream executioner caspases that process a variety of target proteins eventually leading to the apoptotic phenotype. (plantphysiol.org)
  • In mammalians, the release of cytochrome c from mitochondria is a critical step for caspase activation, which is regulated by members for the Bcl‐2 family of proteins. (els.net)
  • In Drosophila , reaper, grim and hid are three Diap1 antagonists, which directly bind Diap1 via the short N ‐terminal peptide motif termed IBM (IAP‐binding motif) present in all three proteins, to release caspases from the negative interaction with Diap1. (els.net)
  • Caspase‐8, in turn, cleaves both effector caspases and Bid, a proapoptotic member of the Bcl‐2 family of proteins. (els.net)
  • In the extrinsic way, the apoptotic signal begins by the union of extra cellular ligands to the surface of cell receptors, resulting in a recruitment of the cytosolic adapter of proteins, that activates the caspase-8 or caspase-10 initiator, and subsequently, the caspases effectors -3, -7 and possibly -6. (thefreedictionary.com)
  • Truncated Bid (tBid) then activates Bax/Bak which induce mitochondrial permeabilisation, the release of cytochrome c , formation of the apoptosome and the activation of caspases 9 and 3. (els.net)
  • Also, 2-EH presented apoptosis induction with characteristic hallmarks, such as loss of mitochondrial membrane potential, caspase activation, DNA fragmentation and cell cycle arrest at the S phase. (scirp.org)
  • For instance, FLIP blocks activation of initiator caspases, Bcl-2 prevents mitochondrial disruption, and X-linked inhibitor of apoptosis protein (XIAP) 3 inhibits downstream caspases (i.e., caspase-9 and caspase-3). (jimmunol.org)
  • In response to cell death stimulation, mitochondrial survivin is rapidly discharged in the cytosol, where it prevents caspase activation and inhibits apoptosis. (jci.org)
  • Fan T, Lu H, Hu H, Shi L, McClarty GA, Nance DM, Greenberg AH, Zhong G (1998) Inhibition of apoptosis in chlamydia-infected cells: blockade of mitochondrial cytochrome c release and caspase activation. (springer.com)
  • Studies on alpha-proteobacteria, closely related species of the free-living ancestor of mitochondria, revealed the presence of genes similar to caspases, suggesting that ancestor of eukaryotic caspases derived from mitochondrial endosymbionts [ 11 ]. (biomedcentral.com)
  • In turn, activated Bid, acting with pX-induced Bax and Noxa, mediates the mitochondrial release of cytochrome c , resulting in the activation of caspase 9 and apoptosis. (asm.org)
  • Caspase-9 is involved in mitochondrial apoptosis pathway and is an initiator caspase. (novusbio.com)
  • Cisplatin or LA-12 enhance killing effects of TRAIL in prostate cancer cells through Bid-dependent stimulation of mitochondrial apoptotic pathway but not caspase-10. (bireme.br)
  • Susin SA, Lorenzo HK, Zamzami N (1999) Mitochondrial release of caspase-2 and -9 during the apoptotic process. (springer.com)
  • Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition," Cell 102:33-42 (2000). (freepatentsonline.com)
  • initiators (activation by receptor cluster) and effectors (activation by mitochondrial permeability transition). (thermofisher.com)
  • Moreover, corosolic acid induced apoptosis mediated by mitochondrial dysfunction and caspase activation. (omicsonline.org)
  • GzmA activates caspase-independent death morphologically identical to apoptosis, characterized by single-stranded DNA damage, mitochondrial dysfunction, and loss of cell membrane integrity, whereas GzmB activates apoptosis by cleaving caspases and some key caspase pathway substrates [3]. (thermofisher.com)
  • The aspartic acid specific protease caspase-9 has been linked to the mitochondrial death pathway. (creativebiomart.net)
  • Furthermore, TCDD was able to trigger BHV-1-induced apoptosis by up-regulating the activation of initiator caspases 8 and 9, as well as of effector caspase 3. (curehunter.com)
  • gondii significantly reduced Fas/CD95-triggered apoptosis in HeLa cells by inhibiting the activities of initiator caspases 8 and 9 and effector caspase 3/7. (curehunter.com)
  • Procaspase-3, a major effector caspase, varied from undetectable to ∼1.6 × 10 6 molecules per cell. (aacrjournals.org)
  • 90 amino acids, whereas an effector caspase contains only 20-30 residues in its prodomain [ 9 ]. (hindawi.com)
  • Additionally, effector caspase activity can cause the nuclear DNA to fragment. (wisegeek.com)
  • Tumor necrosis factor-related apoptosis- inducing ligand (TRAIL) -induced apoptosis, in transformed human breast epithelial MCF-7 cells, resulted in a time-dependent activation of the initiator caspases-8 and -9 and the effector caspase-7. (rupress.org)
  • We tested the role of the P 4 -P 1 recognition motif for caspase specificity by monitoring virus-induced proteolytic processing of Sf-caspase-1, the principal effector caspase of the host insect Spodoptera frugiperda . (pubmedcentralcanada.ca)
  • In contrast, the effector caspase specificity of P35 was unaltered when P35's DQMD motif was replaced with TVTD. (pubmedcentralcanada.ca)
  • These events are associated with increased activity of major initiator (caspase 9) and effector (caspase 3) caspases. (ingentaconnect.com)
  • The caspases mediating apoptosis include initiator caspases 8 and 9 and effector caspase 3 ( 25 ). (asm.org)
  • Similar to Caspase 3 , Caspase-7 is an effector caspase and plays a key role in apoptotic execution. (novusbio.com)
  • FasL expression was up-regulated by taiwanin A at both the transcriptional and translational levels, following the activation of caspase initiator caspase-10 and effector caspase-7. (thefreedictionary.com)
  • Since TCDD activates caspase 3 after 4 h of infection, we have hypothesized an involvement of BHV-1 infected cell protein 0 (bICP0) in this process. (curehunter.com)
  • Activated CASPASE-9 cleaves and activates effector caspases (CASPASE-3, -6, and -7), which are characterized by short prodomains. (prolekare.cz)
  • Activated m-calpain cleaves Bcl-X L and proteolytically activates caspase-12 ( Nakagawa and Yuan, 2000 ). (biologists.org)
  • This procaspase-9 comes and activates caspase-9 and simultaneously this activates procaspase-3 and then activates caspase-3. (thefreelibrary.com)
  • In the second simple pathway, caspase-8 cleaves procaspase-3 directly and activates it. (thefreelibrary.com)
  • When P49's TVTD recognition motif was replaced with P35's DQMD motif, P49 was impaired for inhibition of the initiator caspase that cleaves and activates pro-Sf-caspase-1 and instead formed a stable inhibitory complex with active Sf-caspase-1. (pubmedcentralcanada.ca)
  • Caspase-8 subsequently activates caspase-3, thereby initiating the proteolytic pathway, and ultimately resulting in the apoptotic disassembly of the cell. (haematologica.org)
  • Caspase-9 then activates downstream effector caspases ( 109 ), which in turn act on various cellular substrates to facilitate cellular dismantling ( 110 ). (physiology.org)
  • Granzyme A (GzmA) activates a caspase-independent cell death pathway with morphological features of apoptosis but has unique substrates and mediators [2]. (thermofisher.com)
  • Consistent with this finding, caspase-2 exists as a (p19/p12)2 dimer in solution, even in the absence of substrates or inhibitors. (nih.gov)
  • Second, in tumor cells caspases might be kept in check by cellular caspase inhibitors such as c-FLIP or XIAP. (mdpi.com)
  • The first are initiator caspases, which are regulated by inhibitors. (wisegeek.com)
  • The chapter includes global markets by related products including Caspase Activators and Inhibitors, Protease/Proteasome Inhibitors, Bcl-2 Modulators, p53 Modulators and Other and also by therapeutic areas including Cancer, Neurodegenerative Diseases, Cardiovascular Diseases and other apoptosis based diseases (HIV infection, Organ Transplant Rejection and MODS). (researchimpact.com)
  • The cell death was inhibited completely by treatment with ROS scavengers, but only partly by treatment with caspase inhibitors, expression of Bcl-xL, and knockdown of caspase-3 or Atg-7 which completely inhibits apoptosis or autophagosome formation, respectively, indicating that apoptosis and autophagy-associated cell death are induced simultaneously by the knockdown of caspase-8 expression. (mendeley.com)
  • To advance strategies for selective inhibition of the cell death caspases, we investigated biochemical differences between these baculovirus substrate inhibitors. (pubmedcentralcanada.ca)
  • MNV infection in the presence of caspase inhibitors proceeded via a distinct pathway of rapid cellular necrosis and reduced viral production. (biomedcentral.com)
  • Treatment of RPE cells with caspase inhibitors and Nec-1 resulted in a near complete rescue from cell death. (arvojournals.org)
  • However, inhibitors of these caspases could not protect the cells completely from ALSL-induced apoptosis. (springer.com)
  • This review focuses on the role of antiproliferative agents, specifically mTOR inhibitors, and apoptosis inhibitors, specifically caspase inhibitors, as potential therapies to reduce cyst formation. (asnjournals.org)
  • Intrigued by the multiple ways to control caspase-9's activity, we sought after designing synthetic caspase-9 inhibitors in addition to defining the mechanistic details metal regulation and CARD domain activation. (umass.edu)
  • Through exploring these underlying molecular details behind the various mechanisms, not only has the field of caspase-9 regulation mechanisms been extended, essential information was gained for further pursuit in an advancement towards the design of caspase-9 activators and inhibitors. (umass.edu)
  • Cytotoxic stress, such as that caused by cancer therapies, leads to activation of caspase-2, which acts as a direct effector of the mitochondrion-dependent apoptotic pathway resulting in programmed cell death. (nih.gov)
  • However, the timing or activation sequence of these initiator caspases, which trigger apoptotic pathway, is unclear. (spie.org)
  • A highly specialized class of proteases, termed caspases, are central components of the apoptotic pathway (reviewed in [7] ). (prolekare.cz)
  • Loss of the initiator caspase of the intrinsic apoptotic pathway, caspase-9, however, did not promote cellular transformation. (mdpi.com)
  • Together with our finding that α-toxin induces cytochrome c release in intact cells and, interestingly, also from isolated mitochondria in a Bcl-2-controlled manner, our results demonstrate that S. aureus α-toxin triggers caspase activation via the intrinsic death pathway independently of death receptors. (rupress.org)
  • Caspase activation may proceed through either an external (extrinsic) or internal (intrinsic) death pathway, dependent on the stimulus. (els.net)
  • Thus, activation of an ASK1-FoxO3a-TRADD-caspase 8 pathway participates in the development of neural tube defects, which could be prevented by inhibiting intermediates in this cascade. (sciencemag.org)
  • The MAPK signaling pathway is a three-component module with the MAPK kinase kinase (MAP3K) as the initiator, MAPK kinase (MAPKK), and MAPK. (sciencemag.org)
  • One is the extrinsic pathway, in which ligation of death receptors by death ligands is followed by recruitment of adaptor molecules and activation of caspase-8 or caspase-10. (biologists.org)
  • The other is the intrinsic pathway, in which the release of cytochrome c from mitochondria triggers the formation of the apoptosome composed of Apaf-1, pro-caspase-9, dATP, and cytochrome c . (biologists.org)
  • In the type I pathway, initiator caspases cleave and activate executor caspases directly. (jimmunol.org)
  • In this study, we determined whether TFPI-2 restoration could induce apoptosis through the caspase-mediated signaling pathway. (aacrjournals.org)
  • Basu, Adkins, Basu: Down-regulation of caspase-2 by rottlerin via protein kinase C-delta-independent pathway. (antikoerper-online.de)
  • The cell death protease caspase-2 has recently been recognized as the most apical caspase in the apoptotic cascade ignited during cell stress signaling. (nih.gov)
  • Caspases ( c ysteine- asp artic prote ases , c ysteine asp art ases or c ysteine-dependent asp artate-directed prote ases ) are a family of protease enzymes playing essential roles in programmed cell death (including apoptosis , pyroptosis and necroptosis ) and inflammation . (wikipedia.org)
  • They are named caspases due to their specific cysteine protease activity - a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. (wikipedia.org)
  • According to some studies, susceptibility of cells to anticancer drug-induced apoptosis is markedly inhibited by targeted deletion of genes encoding apoptotic protease activating factor 1 (Apaf-1) or certain caspases. (aacrjournals.org)
  • The knockdown of caspase-8 expression decreased the growth rate and increased cell death, both of which were induced by the absence of protease activity of procaspase-8. (mendeley.com)
  • This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. (genecards.org)
  • Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. (genecards.org)
  • Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. (genecards.org)
  • Cell death via apoptosis is a basic cellular function occurring through the cell death receptor family and their ligands which signal through downstream adaptor molecules and the caspase protease family. (novusbio.com)
  • Caspase 9 (also termed ICE-LAP6, Mch6, Apaf-3) is a member of cysteine protease family of caspases and is encoded by the CASP9 gene in humans. (novusbio.com)
  • The caspases are a group of cysteine protease enzymes essential to apoptosis, inflammation and necrosis. (novusbio.com)
  • Caspase-8 is a member of the aspartate-specific cysteine protease family that is typically synthetized as an inactive zymogen and activated upon an appropriate stimulus. (haematologica.org)
  • Li P, Nijhawan D, Budihardjo I (1997) Cytochrome c and dATP dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. (springer.com)
  • Once released, cytochrome c and procaspase-9 are recruited to apoptosis protease-activating factor 1 (APAF-1) to form the apoptosome holoenzyme complex, which catalyzes the allosteric conformational maturation of procaspase-9 to active caspase-9 ( 1 , 161 , 162 ). (physiology.org)
  • Caspase 6 (CASP6) is a neuron degeneration-related protease and is widely considered to be a potential drug-design target against neurodegenerative diseases such as Huntington's disease and Alzheimer's disease. (iucr.org)
  • A gene on chromosome 2q33-q34 that encodes a protein belonging to the cysteine-aspartic acid protease (caspase) family which, once activated by proteolytic processing, plays a central role in the execution-phase of cell apoptosis, as well as various stages of embryological development. (thefreedictionary.com)
  • Apoptosis is ultimately carried out by the sequential activation of initiator and executioner caspases, which constitute a family of intracellular proteases involved in dismantling the cell in an ordered fashion. (mdpi.com)
  • Apoptosome formation results in the activation of executioner caspases including caspase-3, -6, and -7. (biologists.org)
  • What caspases are "executioner" caspases? (sporcle.com)
  • There are enzymes called executioner caspases that help cells to die in a carefully controlled process called apoptosis. (elifesciences.org)
  • Although the activation of executioner caspases generally leads to apoptosis, there are some circumstances in which cells are able to survive. (elifesciences.org)
  • Here we report the x-ray structure of caspase-2 in complex with the inhibitor acetyl-Leu-Asp-Glu-Ser-Asp-aldehyde at 1.65-A resolution. (nih.gov)
  • The structure reveals the hydrophobic properties of the S5 specificity pocket, which is unique to caspase-2, and provides the details of the inhibitor-protein interactions in subsites S1-S4. (nih.gov)
  • In Drosophila , the inhibitor of apoptosis protein 1 (DIAP1) is known to ubiquitylate the initiator caspase DRONC in vitro . (prolekare.cz)
  • In all of the neuronal populations studied here (hippocampal neurons, sympathetic neurons, and PC12 cells), cell death was blocked by the broad spectrum caspase inhibitor N -benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone and more specifically by the downregulation of caspase-2 with antisense oligonucleotides. (jneurosci.org)
  • The caspase 3 substrate Ac-Asp-Glu-Val-Asp p -nitroanilide (Ac-DEVD- p NA), the pancaspase inhibitor (benzyloxycarbonyl-Val-Ala-Asp, Z-VAD-FMK), the caspase 3 inhibitor (Z-DEVD-FMK), the proteasome inhibitor (MG-132), dihydroethidium (DHE), and 2′,7′-dichlorofluorescine diacetate (H 2 DCFDA) were from Calbiochem. (pnas.org)
  • Caspase activity was verified with the fluorochrome-labeled inhibitor of caspases (FLICA) probe specific for each caspase. (arvojournals.org)
  • Caspase 3 is a cytoplasmic caspase with two isoforms (one acts as a dominant negative inhibitor), and is involved in the activation cascade for apoptosis execution. (novusbio.com)
  • The FAAH inhibitor N-arachidonoylserotonin increased colon endocannabinoid levels, reduced ACF formation, and partially normalized cleaved caspase-3 (but not caspase-9) expression. (420magazine.com)
  • This activated protein can then go on to cleave and activate further caspases, initiating the caspase cascade. (wikipedia.org)
  • A hierarchy of caspase activation exists whereby initiator caspases become activated to cleave and activate effector caspases. (els.net)
  • Because DRONC protein accumulates in diap1 mutant cells that are kept alive by caspase inhibition ("undead" cells), it is thought that DIAP1-mediated ubiquitylation causes proteasomal degradation of DRONC, protecting cells from apoptosis. (prolekare.cz)
  • Note that in addition to apoptosis, Caspase-8 is also required for the inhibition of another form of programmed cell death called Necroptosis . (wikipedia.org)
  • Caspase 8 then cleaves RIPK1, leading to inhibition of this signalling, inhibiting cell death. (wikipedia.org)
  • In this work, we expand on our previous work with DEHP and screen the 2-EH metabolite for different cell death endpoints such as growth inhibition, apoptosis, autophagy, caspase activation, DNA fragmentation, and cell cycle arrest using fluorophores and the NC3000 instrument. (scirp.org)
  • We concluded that the TVTD recognition motif is required but not sufficient for initiator caspase inhibition by P49. (pubmedcentralcanada.ca)
  • Because selective inhibition of caspases may be advantageous in therapeutics for apoptosis-associated diseases, the molecular basis of target specificity by P49 and P35 is of considerable interest. (pubmedcentralcanada.ca)
  • All potently blocked caspases-1, -4, -5 and -8 activity but exhibited negligible inhibition of caspases-2, -3 and -6. (portlandpress.com)
  • Both in vitro and in vivo studies suggest that caspase or apoptosis inhibition attenuates cyst formation. (asnjournals.org)
  • Inhibition of caspase activity in wing discs reduced wing size demonstrating functional significance. (elifesciences.org)
  • After Src kinase inhibition followed by hypoxia, caspase-2 expression was similar to normoxia levels. (ovid.com)
  • Based on known mechanisms, such as the unique inhibitory complex of caspase-9 and XIAP-BIR3, development of synthetic regulators can be envisioned, while other mechanisms such as zinc-mediated inhibition and CARD activation of caspse-9 remain undefined. (umass.edu)
  • Complex formation allows proteolytic activation of procaspase into the active caspase form which results in the initiation of apoptosis (cell death). (wikipedia.org)
  • The central component of this machinery is a proteolytic system involving a family of proteases called caspases. (sciencemag.org)
  • Because relatively little is known about caspase regulation, it is instructive to first review lessons learned from well-studied proteolytic systems, which provide a framework for understanding the biology of caspases and can serve as guiding principles for ongoing research in this area. (sciencemag.org)
  • Activation of caspase-3 requires proteolytic processing of its inactive zymogen into activated p17 and p12 fragments. (cellsignal.com)
  • Activation of caspases requires proteolytic processing at conserved internal asp. (genecards.org)
  • Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. (genecards.org)
  • It is tempting to speculate that comparable caspase-mediated proteolytic events cause the apoptotic phenotype observed in dying plant cells. (plantphysiol.org)
  • Caspases are synthesized as inactive pro-enzymes and are activated by directed proteolysis that removes the N-terminal peptide and cleaves the proteolytic domain at specific recognition sites (Fig. 1 ). (plantphysiol.org)
  • The intersubunit disulfide bridge stabilizes the dimeric form of caspase-2, whereas all other long prodomain caspases exist as monomers in solution, and dimer formation is driven by ligand binding. (nih.gov)
  • The full-length form (zymogen) of caspases is catalytically inactive and consists of a prodomain, a large and a small subunit. (prolekare.cz)
  • Based on the length of the prodomain, caspases are divided into initiator (also known as apical or upstream) and effector (also known as executioner or downstream) caspases [7] . (prolekare.cz)
  • Caspases, a family of c ysteinyl a spartate- s pecific p rote ases , are synthesized as zymogens with a prodomain of variable length followed by a large subunit (p20) and a small subunit (p10). (jci.org)
  • Depending on the structure of the prodomain and their function, caspases are typically divided into 3 major groups (Figure 1 A). The caspases with large prodomains are referred to as inflammatory caspases (group I) and initiator of apoptosis caspases (group II), while caspases with a short prodomain of 20-30 amino acids are named effector caspases (group III). (jci.org)
  • All caspases are produced as catalytically inactive zymogens or proenzymes containing a prodomain, a large (p20) and a small subunit (p10). (els.net)
  • The prodomain of the initiator (also known as apical) caspases (2, 8, 9 and 10) is much longer than that of effector caspases 3, 6 and 7. (els.net)
  • Once active, initiator caspases proteolytically cleave effector caspases at distinct aspartate residues, to release the prodomain, large and small subunits. (els.net)
  • It was proposed that the "initiator" caspases with a long prodomain, such as caspases 8, 9, and 10, directly or indirectly activate the "effector" caspases, such as caspases 3, 6, and 7 ( Cohen, 1997 ). (aspetjournals.org)
  • A, Caspases are synthesized as inactive pro-enzymes with an N-terminal prodomain and a large and small subunit of 17 to 21 and 10 to 13 kD, respectively. (plantphysiol.org)
  • Two FRET probes were constructed that each encoded a CRS (caspase-2 or caspase-9 recognition Site) fused with a cyan/yellow fluorescent protein (CFP/YFP) and a red fluorescent protein (DsRed) (CFP/YFP-CRS-DsRed). (spie.org)
  • Through homotypic CARD/CARD interactions with the adapter protein APAF-1, CASPASE-9 is recruited into the apoptosome, a large multi-subunit complex, where it dimerizes and auto-processes leading to its activation [8] , [9] . (prolekare.cz)
  • Furthermore, α-toxin-induced caspase activation in CD95-resistant Jurkat sublines lacking CD95, Fas-activated death domain, or caspase-8 but not in cells stably expressing the antiapoptotic protein Bcl-2. (rupress.org)
  • Outcomes Caspase-8 interacts with CrkL SH2 domains We observed the de novo phosphorylation of many protein, in caspase-8 showing cells selectively, pursuing cell adhesion to fibronectin substrates. (acancerjourney.info)
  • To determine whether the phosphoprotein may end up being component of a complicated linked with the caspase, caspase-8 immunoprecipitations had been performed by us, solved the necessary protein and probed the precipitates with a -panel of cytoskeletal and apoptotic antibodies, including one that regarded Crk family members necessary protein. (acancerjourney.info)
  • Identity of an connections between Crk and Caspase-8 protein. (acancerjourney.info)
  • ASK1 activation stimulated the activity of the transcription factor FoxO3a, which increased the abundance of the apoptosis-promoting adaptor protein TRADD, leading to activation of caspase 8. (sciencemag.org)
  • Molecular basis of cytotoxicity of Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) in EBV latency III B cells: LMP1 induces type II ligand-independent autoactivation of CD95/Fas with caspase 8-mediated apoptosis. (nih.gov)
  • Using transient transfection of COOH-terminal-tagged green fluorescent protein fusion constructs, caspases-3, -7, and -8 were localized throughout the cytoplasm of MCF-7 cells. (rupress.org)
  • Activation of caspases during apoptosis is triggered by adaptor protein-mediated oligomerization of initiator procaspases. (sciencemag.org)
  • Here we describe such a caspase activation system that is based on FK506 binding protein (FKBP)-mediated oligomerization. (sciencemag.org)
  • The discovery of p35, a baculovirus protein inhibiting caspase activity, has led to the characterization of the first lepidopteran caspase, Sf-Caspase-1. (biomedcentral.com)
  • Live cell imaging and activity-based protein profiling showed that activation of caspase-like proteases occurred within two hours of infection, followed by morphological changes to the cells. (biomedcentral.com)
  • CASP8 (Caspase 8) is a Protein Coding gene. (genecards.org)
  • Triggering of the Fas receptor with its cognate ligand or agonistic antibody results in receptor trimerization and recruitment of Fas receptor-associated protein with death domains (FADD), which in turn binds to the death effector domains in the N-terminal region of caspase 8, resulting in its activation. (aspetjournals.org)
  • The activation of effector caspases occurs downstream of the activation of initiator caspases (CED‐3, Dronc and caspase‐9), which occurs on the formation of the apoptosome, a protein complex contaning CED‐4, Ark/Dark and Apaf‐1, and cytochrome c . (els.net)
  • Human Caspase 9 recombinant protein catalytic subunits (NP_001220). (novusbio.com)
  • Zusätzlich bieten wir Ihnen Caspase 2 Kits (30) und Caspase 2 Proteine (24) und viele weitere Produktgruppen zu diesem Protein an. (antikoerper-online.de)
  • IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs," Cancer Research 58:5315-5320 (1998). (freepatentsonline.com)
  • To document systematically where and when cells survive caspase-3 activation in vivo, we designed a system, CasExpress, which drives fluorescent protein expression, transiently or permanently, in cells that survive caspase-3 activation in Drosophila. (elifesciences.org)
  • The experiments used a new method that results in cells that survive caspase activity producing a fluorescent marker protein. (elifesciences.org)
  • We conclude that hypoxia results in increased expression of caspase-2 protein in the cytosolic fraction of the cerebral cortex of the newborn piglets. (ovid.com)
  • CASP10 is an initiator-type caspase which is activated by, and interacts with, upstream adaptor molecules through CARD and DED protein-protein interaction domains. (thefreedictionary.com)
  • Once in the cytoplasm, GzmB targets multiple protein substrates, resulting eventually into apoptotic demise of the target cell both in caspase-dependent and independent manners. (thermofisher.com)
  • Ho, P.K. & Hawkins, C.J. Mammalian initiator apoptotic caspases. (nature.com)
  • Caspases were implicated in apoptosis with the discovery that CED-3, the product of a gene required for cell death in the nematode Caenorhabditis elegans , is related to mammalian interleukin-1β-converting enzyme (ICE or caspase-1) ( 2 , 3 ). (sciencemag.org)
  • The orthologs differed markedly in their propensity to inhibit non-mammalian caspases. (portlandpress.com)
  • Schematic representation of structural features of mammalian caspases. (plantphysiol.org)
  • Besides their function in apoptosis, some members of the caspase family participate in the processing of proinflammatory cytokines [ 8 ]. (hindawi.com)
  • Cell death signals are transduced by death domain containing adapter molecules and members of the caspase family of proteases. (novusbio.com)
  • Despite sharing some common features, other aspects of the biochemistry, substrate specificity, regulation and signaling mechanisms differ between initiator apoptotic caspases. (edu.au)
  • Structure and activation of apoptotic caspases. (els.net)
  • Cytochrome c released from mitochondria is coupled to the activation of caspase-9, a key initiator caspase (1). (cellsignal.com)
  • Both pro and active/cleaved Caspase-9 staining may also be seen in the mitochondria. (novusbio.com)
  • In cancer, therefore, one would anticipate caspases to be frequently rendered inactive, either by gene silencing or by somatic mutations. (mdpi.com)
  • Caspases are synthesised as inactive zymogens (pro-caspases) that are only activated following an appropriate stimulus. (wikipedia.org)
  • Caspases are synthesized as inactive proenzymes and proteolytically processed to form an active complex composed of two heterodimeric subunits of ∼10 and 20 kD. (rupress.org)
  • Caspases proteolytically cleave a host of cellular substrates at aspartate residues, which may render them either functionally inactive or confer novel activities that help to promote cellular demise. (els.net)
  • To keep the cells from self-destructing, caspases are kept in an inactive state. (wisegeek.com)
  • The active initiator caspases cleave the inactive effector caspases, which then activate apoptosis. (wisegeek.com)
  • 2. Caspase antibodies are classical tools for detecting inactive (pro) and active (cleaved) forms of the enzymes. (novusbio.com)
  • Caspases are cysteine proteases, expressed as inactive precursors, that mediate apoptosis by proteolysis of specific substrates. (thermofisher.com)
  • Subsequently, active caspases specifically process various substrates that are implicated in apoptosis and inflammation. (jci.org)
  • The large and small subunit associate with each other to form an active heterodimer caspase. (wikipedia.org)
  • Caspases are proteolytically cleaved at specific aspartate residues, generating a large and small subunit that together form the active enzyme. (rupress.org)
  • In western blots, the proform of caspase-9 is detected at ~50 kDa, the large subunit at ~35 kDa, and the small subunit at ~15 kDa. (novusbio.com)
  • The three effector caspases are expressed as dimeric zymogens and each monomer contains a short pro-domain, a large subunit (p20), an intersubunit linker (L) and a small subunit (p10). (iucr.org)
  • The activated effector caspases then cleave intracellular substrates, such as poly(ADP-ribose) polymerase (PARP) and lamins, during the execution phase. (aspetjournals.org)
  • GzmB-activated caspase-3 results in the processing of several cellular substrates integral to eliciting the apoptotic phenotype. (thermofisher.com)
  • Herein, apoptosis and/or non-apoptotic functions of caspases may even promote tumor development. (mdpi.com)
  • In this Review, we discuss the structures and functions of caspases as well as their role in novel approaches for treating cancer, autoimmune diseases, degenerative disorders, and stroke. (jci.org)
  • This FKBP-based system may be widely applicable to the study of the regulation and functions of caspases. (sciencemag.org)
  • Non-apoptotic functions of caspases in cellular proliferation and differentiation. (semanticscholar.org)
  • When released, cytosolic cytochrome c binds together with dATP and the apoptosis-activating factor-1 to pro-caspase-9 to form the apoptosome. (rupress.org)
  • Cytoplasmic cytochrome c drives the formation of the apoptosome and activation of initiator caspase 9. (els.net)
  • Supplied in SDS sample buffer.Caspase-3 Control Cell Extracts (Jurkat +Cytochrome c): Untreated Jurkat cells are lysed in Chaps cell extract buffer and a cytoplasmic fraction is generated. (cellsignal.com)
  • In Drosophila , the importance of cytochrome c and Bcl‐2 family members (Debcl/Buffy) for apoptosome formation and caspase activation is still not clear. (els.net)
  • Furthermore, activation of caspase-1 in response to an intracellular pathogen (Salmonella typhimurium) was abrogated severely in ASC-null macrophages. (nih.gov)
  • These data show that whereas ASC is key to caspase-1 activation within the inflammasome, Ipaf provides a special conduit to the inflammasome for signals triggered by intracellular pathogens. (nih.gov)
  • Previously, we have shown that brain hypoxia-induced production of caspases 1, 3, 8, and 9 is Src kinase mediated, a nonreceptor intracellular family of kinases. (ovid.com)
  • Although caspase-1 has no obvious role in cell death, it has become the first identified member of a large family of proteases whose members have distinct roles in inflammation and apoptosis ( Fig. 1 A). In apoptosis, caspases function in both cell disassembly (effectors) and in initiating this disassembly in response to proapoptotic signals (initiators). (sciencemag.org)
  • The caspases are a family of cysteinyl aspartate-specific proteases that are critical effectors of apoptosis in metazoans (reviewed in references 15 , 23 , 32 , and 33 ). (pubmedcentralcanada.ca)
  • These enzymes can be divided into initiators and effectors. (genecards.org)
  • Auf www.antikoerper-online.de finden Sie aktuell 236 Caspase 2, Apoptosis-Related Cysteine Peptidase (CASP2) Antikörper von 34 unterschiedlichen Herstellern. (antikoerper-online.de)
  • This Review gives an overview of caspases and their classification, structure, and substrate specificity. (jci.org)
  • It contains a fluorogenic substrate (N-Acetyl-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin or Ac-DEVD-AMC) for caspase-3. (cellsignal.com)
  • During the assay, activated caspase-3 cleaves this substrate between DEVD and AMC, generating highly fluorescent AMC that can be detected using a fluorescence reader with excitation at 380 nm and emission between 420 - 460 nm. (cellsignal.com)
  • The substrate specificity of initiator caspases differs from that of effector caspases, due in part to their unique functions during execution of apoptosis ( 37 ). (pubmedcentralcanada.ca)
  • Furthermore, an interaction was discovered between CARD and the catalytic core of caspase-9 in the presence of a properly formed substrate binding groove, a potential mechanism utilized by the apoptosome for activation of the enzyme. (umass.edu)
  • One of the major substrate of GzmB is Pro-caspase-3. (thermofisher.com)
  • These changes reflect complex biochemical events carried out by a family of cysteine proteases called caspases. (sciencemag.org)
  • Evolutionarily conserved proteases, called caspases, play a central role in regulating apoptosis. (biomedcentral.com)
  • A major family of evolutionarily conserved cysteine-dependent aspartate-specific proteases, called caspases, plays a central role in apoptosis. (biomedcentral.com)
  • In animal systems PCD is synonymous with apoptosis, a cell death process characterized by a distinct set of morphological and biochemical features, mediated by a class of specific Cys proteases called cysteinyl aspartate-specific proteinases (caspases). (plantphysiol.org)
  • A subtype of caspases that contain long pro-domain regions that regulate the activation of the enzyme. (curehunter.com)
  • Structure of caspase-1 (CASP1), originally called interleukin-1 beta-converting enzyme (ICE), the first human caspase to be identified. (wikipedia.org)
  • The active enzyme often exists as a heterotetramer in the biological environment, where a pro-caspase dimer is cleaved together to form a heterotetramer. (wikipedia.org)
  • The adaptors ASC, Ipaf and RIP2 have each been proposed to regulate caspase-1 (also called interleukin (IL)-1 converting enzyme), which is activated within the 'inflammasome', a complex comprising several adaptors. (nih.gov)
  • These cleavages remove an -N[H.sub.2] peptide terminal and separate the small and large domains of the pro-enzyme so that it produces the mature hetero tetrameric caspases containing two large and two small domains. (thefreelibrary.com)
  • The cleaved caspase-3 can be detected by antibodies specific for this cleaved enzyme (p17 fragment) in cell lysates by immunoblotting or by an ELISA assay utilizing spectrophotometric determination with a microplate reader at OD450 nm. (clinicaltrials.gov)
  • All in all, the regulation of caspase-9 occurs on a variety of levels that requires almost every surface of the enzyme. (umass.edu)
  • FADD again recruits procaspase 8, which initiates the caspase cascade leading to apoptosis. (wikipedia.org)
  • Because synaptic loss, neuritic changes, and cell loss are all features of Alzheimer's disease, activation of the apoptotic cascade, especially the activation of caspases, could explain many of the features of the disease and its progression. (jneurosci.org)
  • The formation of active caspases forms a cascade in which initiator caspases (8, 9) interact with the downstream effector molecules (3, 7) to facilitate their own activation. (thefreelibrary.com)
  • Studies on Sf-Caspase-1 mode of activation suggested that apoptosis in Lepidoptera requires a cascade of caspase activation, as demonstrated in many other species. (biomedcentral.com)
  • Seems to be linked to an activation cascade of caspases (aspartate-specific cysteine proteases) responsible for apoptosis execution. (genecards.org)
  • CASP2_HUMAN ] Involved in the activation cascade of caspases responsible for apoptosis execution. (proteopedia.org)
  • The long prodomains of initiator caspases harbor regulatory motifs such as the caspase activation and recruitment domain (CARD) in CASPASE-9. (prolekare.cz)
  • Within their long prodomains, caspases-2, -9 and -12 contain a caspase activation and recruitment domain while caspases-8 and -10 bear death effector domains. (edu.au)
  • Caspase prodomains. (jci.org)
  • Almost all variants retained the ability to inhibit caspase-1, but many lacked caspase-8 inhibitory activity. (portlandpress.com)
  • IAPs (in mammalians) or Diap1 (in Drosophila ) directly bind to caspases via their BIR (baculovirus inhibitory repeat) domains, to inhibit caspase activity. (els.net)
  • The data demonstrate that cell death is prevented during mitosis through the inhibitory phosphorylation of caspase-2 and suggest that under conditions of mitotic arrest, cdk1-cyclin B1 activity must be overcome for apoptosis to occur. (antikoerper-online.de)
  • We report the first stabilized α-helical peptides that harness the native regulatory mechanism of caspase-9 and the BIR3 domain which lead to the understanding of the importance of exosites in inhibitory complexes. (umass.edu)
  • First, caspase-1 induces the activation and secretion of the two prominent pro-inflammatory cytokines, interleukin-1β (IL-1β) and IL-18. (nih.gov)
  • A family of cysteinyl aspartate-specific proteases (caspases) induces dramatic biochemical and morphological changes during apoptosis. (utexas.edu)
  • Upon formation of the death-inducing signaling complex or the apoptosome, pro-caspase-8 or -9, respectively, are autoproteolytically processed, resulting in the activation of downstream caspases. (rupress.org)
  • Procaspase-8, the zymogen type of the apoptosis-initiator caspase-8, undergoes phosphorylation following integrin-mediated cell connection to an extracellular matrix base. (acancerjourney.info)
  • As of 2009, there are 11 or 12 confirmed caspases in humans [note 1] and 10 in mice, carrying out a variety of cellular functions. (wikipedia.org)
  • Activation of Caspases ensures that the cellular components are degraded in a controlled manner, carrying out cell death with minimal effect on surrounding tissues . (wikipedia.org)
  • CrkL (and knockouts display cardiac and sensory crest flaws, ending in embryonic lethality.17,18 Here, we offer proof that caspase-8 interacts with the You will need2 domains of CrkL in a Src- and adhesion-dependent way, and that this connections stimulates cellular migration. (acancerjourney.info)
  • Caspases target multiple aspects of the cellular architecture to induce collapse of organelles and the cytoskeleton. (els.net)
  • Signalling networks that regulate cellular processes critical for cell survival are inactivated by caspases. (els.net)
  • We are studying the proliferative role of caspases to better understand the interplay between cellular life and death processes. (upenn.edu)
  • Tight regulation of caspase-9, a key initiator of apoptosis, is required to uphold cellular homeostasis. (umass.edu)
  • Once initiated caspase-9 goes on to cleave procaspase-3 & procaspase-7 and which cleave several cellular targets, including poly ADP ribose polymerase. (creativebiomart.net)
  • These features form the basis of caspase-2 specificity and allow the design of caspase-2-directed ligands for medical and analytical use. (nih.gov)
  • The molecular basis of this novel caspase specificity is unknown. (pubmedcentralcanada.ca)
  • Our findings demonstrate a critical role for the P 4 -P 1 recognition site in caspase specificity by P49 and P35 and indicate that additional determinants are involved in target selection. (pubmedcentralcanada.ca)
  • We compared the caspase specificity of CrmA to three orthologs from orthopoxviruses and four from more distant chordopoxviruses. (portlandpress.com)
  • Caspase-8 has an important role as an initiator caspase during death receptor-mediated apoptosis. (mendeley.com)
  • The initiator isoforms are activated by, and interact with, upstream adaptor molecules. (genecards.org)
  • In addition, only initiator caspases contain a caspase recruitment domain (CARD) or death effector domain (DED) preceding the catalytic domain. (hindawi.com)
  • There are several types of caspases that have different functions in causing apoptosis. (wisegeek.com)
  • Not surprisingly, because of their central role in cell death, both types of caspases are important therapeutic targets for the treatment of apoptosis-associated diseases ( 11 , 23 ). (pubmedcentralcanada.ca)
  • The basic repertoire of five major types of caspases shared among Lepidoptera seems to be smaller than for most other groups studied to date, but gene duplication still plays a role in lineage-specific increases in diversity, just as in Diptera and mammals. (biomedcentral.com)
  • These data refine current models of caspase regulation by IAPs. (prolekare.cz)
  • Understanding caspase regulation is intimately linked to the ability to rationally manipulate apoptosis for therapeutic gain. (sciencemag.org)
  • Alterations in the regulation of apoptosis can lead to cancer or autoimmune disease, so there is much interest in better understanding the biochemistry and genetics of caspase activation in human cells using more simple organisms. (wisegeek.com)
  • Its caspases display regulation by nucleotides that is consistent with `applying the brakes' to cell death during energy limitation. (biologists.org)
  • Using a different set of approaches, the up-regulation of caspases, DNA condensation/fragmentation, and membrane blebbing, all of which are markers of apoptosis, were confirmed. (biomedcentral.com)
  • This balance is achieved, in part, through the precise regulation of apoptosis, which involves complex molecular events that ultimately activate, or prevent the activation of caspases (cysteine‐aspartic acid proteases). (els.net)
  • 1 Additionally, caspase-8 is also essential for various immune processes, such as lymphocyte activation, inflammasome regulation and cytokine production. (haematologica.org)
  • Initiator caspases (including 8, 9, 10 and 12) are closely coupled to proapoptotic signals. (cellsignal.com)
  • Proapoptotic signals autocatalytically activate initiator caspases, such as Caspase-8 and Caspase 9. (thermofisher.com)
  • Caspases also have a role in inflammation, whereby it directly processes pro-inflammatory cytokines such as pro-IL1β. (wikipedia.org)
  • [5] Caspases involved with processing inflammatory signals are also implicated in disease. (wikipedia.org)
  • The enzymes are sub classified into three types: Initiator, Executioner and Inflammatory. (wikipedia.org)
  • Inflammatory caspases play a central role in innate immunity by responding to cytosolic signals and initiating a twofold response. (nih.gov)
  • Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. (springer.com)
  • This results in the generation of mature active caspases that consist of the heterotetramer p20 2 -p10 2 . (jci.org)
  • Knockdown of caspase-8 or CrkL utilized lentivirus (Open up Biosystems) and verified by immunoblot with particular antibodies below. (acancerjourney.info)
  • We also demonstrated that caspase-12 was processed downstream of Apaf-1 and caspase-3, and neither overexpression nor knockdown of caspase-12 affected susceptibility of the cells to ER stress-induced cell death. (biologists.org)
  • To elucidate critical signaling network properties, we examined the effects of altering the level of Bcl-2 on the kinetics of caspase-3 activation, using both overexpression and knockdown in the model and experimentally. (jimmunol.org)
  • Moreover, although Bcl-2 overexpression strongly reduces caspase-3 activation, Bcl-2 knockdown has a negligible effect, demonstrating a general model finding that varying the expression levels of signal molecules frequently has asymmetric effects on the outcome. (jimmunol.org)
  • Small interfering RNA-mediated caspase-2 knockdown neuroprotected RGC around but not in the center of the injury site. (arvojournals.org)
  • In addition, caspase-2 knockdown increased the amplitude of the ERG photopic negative response (PhNR) at 2 weeks after injury. (arvojournals.org)
  • These initiator caspases then cleave and in turn activate downstream effector caspases such as caspases-3, -6 and -7. (clinicaltrials.gov)
  • The effector caspases inhibit the enzymes that repair damaged DNA. (wisegeek.com)
  • Although related, P49 and P35 inhibit initiator and effector caspases, respectively, during infection of permissive insect cells. (pubmedcentralcanada.ca)
  • We show that caspase activation and DNA fragmentation were induced not only when Jurkat T cells were infected with intact bacteria, but also after treatment with supernatants of various S. aureus strains. (rupress.org)
  • Out of the complex DFF40 and DFF45 (DNA fragmentation factor 45), the caspase-3 cleaves DFF45 and as a result of that, DFF45 dissociates from DFF40, causing oligomerization of DFF40 which has DNase activity. (thefreelibrary.com)
  • Caspase activity is due to a group of very complex enzymes that regulate programmed cell death, or apoptosis , in multicellular organisms. (wisegeek.com)
  • Cleaves caspase-3, -7, -9 and 10 to give rise to active enzymes mediating apoptosis. (genecards.org)
  • Lep-Caspase-2 is absent from the silkworm genome and appears to be noctuid-specific, and to have arisen from a tandem duplication of the Caspase-1 gene. (biomedcentral.com)
  • Caspase-9 is an initiator caspase encoded by the CASP9 gene. (creativebiomart.net)
  • These data suggest parallel activation of initiator caspase-2 and caspase-9 in cisplatin-induced cell death. (spie.org)
  • Finally, caspase-independent cell death mechanisms might abrogate the selection pressure for caspase inactivation during tumor development. (mdpi.com)
  • Moreover, experimental evidence suggests that caspases might play non-apoptotic roles in processes that are crucial for tumorigenesis, such as cell proliferation, migration, or invasion. (mdpi.com)
  • Caspases are the proteases responsible for dismantling the cell in an ordered and histologically distinct process termed apoptosis [ 1 ]. (mdpi.com)
  • Caspases have other identified roles in programmed cell death such as pyroptosis and necroptosis . (wikipedia.org)
  • There are other identified roles of caspases such as cell proliferation, tumour suppression, cell differentiation, neural development and axon guidance and ageing. (wikipedia.org)
  • [5] Conversely, over-activation of some caspases such as caspase -3 can lead to excessive programmed cell death. (wikipedia.org)
  • [5] The integral role caspases play in cell death and disease has led to research on using caspases as a drug target. (wikipedia.org)
  • Most caspases play a role in programmed cell death. (wikipedia.org)
  • Caspase-14 plays a role in epithelial cell keratinocyte differentiation and can form an epidermal barrier that protects against dehydration and UVB radiation. (wikipedia.org)
  • Apaf-1 and procaspase-9, which are implicated in caspase activation after treatment of cells with various anticancer drugs, were detectable in all of the cell lines, with levels of Apaf-1 ranging from ∼1 × 10 5 to 2 × 10 6 molecules per cell and procaspase-9 from ∼5 × 10 3 to ∼1.6 × 10 5 molecules per cell. (aacrjournals.org)
  • With the exception of caspase-3, all of the components of the core cell-death machinery are expressed in all of the cell lines examined. (aacrjournals.org)
  • We also demonstrate that S. aureus -induced cell death and caspase activation were mediated by α-toxin, a major cytotoxin of S. aureus , since both events were abrogated by two different anti-α-toxin antibodies and could not be induced with supernatants of an α-toxin-deficient S. aureus strain. (rupress.org)
  • We also describe the current knowledge of how interference with caspase signaling can be used to pharmacologically manipulate cell death. (jci.org)
  • Biochemical analyses showed that T lymphocytes with the deletion variant had lower caspase-8 activity and activation-induced cell death upon stimulation with cancer cell antigens. (nature.com)
  • Siegel, R.M. Caspases at the crossroads of immune-cell life and death. (nature.com)
  • In this review, we describe properties of caspases, how they kill a cell, how they are regulated, and discuss the potential therapeutic utility of caspase modulation. (sciencemag.org)
  • Second, either caspase-1 or caspase-11 can trigger a form of lytic, programmed cell death called pyroptosis. (nih.gov)
  • The Caspase-3 Activity Assay Kit is a fluorescent assay that detects the activity of caspase-3 in cell lysates. (cellsignal.com)
  • Toxoplasma gondii inhibits Fas/CD95-triggered cell death by inducing aberrant processing and degradation of caspase 8. (nih.gov)
  • Caspase-3 is a component of Fas death-inducing signaling complex in lipid rafts and its activity is required for complete caspase-8 activation during Fas-mediated cell death. (nih.gov)
  • In this report, we show that caspase-8 has an essential role in cell survival in mouse T-lymphoma-derived L5178Y cells. (mendeley.com)
  • The cell death was associated with reactive oxygen species (ROS) accumulation, caspase activation, and autophagosome formation. (mendeley.com)
  • Caspases constitute a family of cysteine proteases centrally involved in programmed cell death, which is an integral part of normal embryonic and fetal development. (sigmaaldrich.com)
  • However, it has become clear that specific caspases also have functions independent of cell death. (sigmaaldrich.com)
  • P49 and P35 are two baculovirus-encoded apoptotic suppressors that function by inhibiting a broad range of the cell death proteases known as caspases ( 2 , 3 , 19 , 30 , 40 , 45 ). (pubmedcentralcanada.ca)
  • Although related to one another, P49 and P35 display different caspase specificities in the infected insect cell ( 21 , 22 , 45 ). (pubmedcentralcanada.ca)
  • Paradoxically, some caspases are also involved in cell proliferation. (upenn.edu)
  • Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. (genecards.org)
  • Although to date no functional homologs of animal caspases have been identified in plants, a vast amount of indirect evidence suggesting the existence in plants of true caspase-like activity and its functional involvement in plant cell death has accumulated. (plantphysiol.org)
  • Initiator caspases may be activated by autoprocessing when clustering occurs e.g. at the cytosolic part of (activated) cell death receptors. (plantphysiol.org)
  • The activation of caspases is, in most cases, irreversible and represents the commitment to the cell death fate. (els.net)
  • Caspase-2-dependent cell death is important and evidenced in models of RGC degeneration. (arvojournals.org)
  • Some cells activated caspase-3 during their normal development in every cell and in every animal without evidence of apoptosis. (elifesciences.org)
  • For some types of cells, every cell seemed to survive caspase activity with no evidence of apoptosis. (elifesciences.org)
  • cell survival following caspase activation has been described (e.g. (elifesciences.org)
  • Activated initiator caspases then process effector caspases, such as Caspase-3 and Caspase-7, which in turn cause cell collapse. (thermofisher.com)
  • Caspases function in autophagic programmed cell death in Drosophila. (semanticscholar.org)