Caspases: 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.Caspase Inhibitors: Endogenous and exogenous compounds and that either inhibit CASPASES or prevent their activation.Apoptosis: 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.Caspase 6: 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.Caspase 3: 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.Caspase 7: 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.Caspases, Initiator: 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.Amino Acid Chloromethyl Ketones: Inhibitors of SERINE ENDOPEPTIDASES and sulfhydryl group-containing enzymes. They act as alkylating agents and are known to interfere in the translation process.Caspase 9: 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.RNA, Transfer, Met: 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).Cysteine Proteinase Inhibitors: Exogenous and endogenous compounds which inhibit CYSTEINE ENDOPEPTIDASES.Codon, Initiator: 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.Caspases, Effector: 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.Caspase 8: 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.Caspase 2: 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.Enzyme Activation: 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.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Molecular Sequence Data: 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.Peptide Chain Initiation, Translational: 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.X-Linked Inhibitor of Apoptosis Protein: 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.Inhibitor of Apoptosis Proteins: 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.Mitochondria: 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)Apoptotic Protease-Activating Factor 1: 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.Proto-Oncogene Proteins c-bcl-2: 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.Cytochrome c Group: 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)Antigens, CD95: 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.DNA Fragmentation: 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.Caspase 10: 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.Caspase 1: 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.Replication Origin: 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 c: 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.Cysteine Endopeptidases: 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.Jurkat Cells: A CELL LINE derived from human T-CELL LEUKEMIA and used to determine the mechanism of differential susceptibility to anti-cancer drugs and radiation.Poly(ADP-ribose) Polymerases: 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.DNA Replication: The process by which a DNA molecule is duplicated.Amino Acid Sequence: 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.DNA-Binding Proteins: 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.TATA Box: 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.Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability.Plasmids: 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.RNA, Transfer: 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.Hydroxymethyl and Formyl Transferases: Enzymes that catalyze the transfer of hydroxymethyl or formyl groups. EC 2.1.2.Apoptosomes: 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.BH3 Interacting Domain Death Agonist Protein: A member of the Bcl-2 protein family that reversibly binds MEMBRANES. It is a pro-apoptotic protein that is activated by caspase cleavage.bcl-2-Associated X Protein: 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.Escherichia coli: 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.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Transcription, Genetic: The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.Prokaryotic Initiation Factor-2: 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.HeLa Cells: 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.Signal Transduction: 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.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Enzyme Precursors: Physiologically inactive substances that can be converted to active enzymes.DNA Helicases: 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.Nucleic Acid Conformation: The spatial arrangement of the atoms of a nucleic acid or polynucleotide that results in its characteristic 3-dimensional shape.Promoter Regions, Genetic: 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.Oligopeptides: Peptides composed of between two and twelve amino acids.Apoptosis Regulatory Proteins: 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.Fas-Associated Death Domain Protein: 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.Peptide Initiation Factors: Protein factors uniquely required during the initiation phase of protein synthesis in GENETIC TRANSLATION.Mutation: 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.Proteins: 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.Protein Biosynthesis: The biosynthesis of PEPTIDES and PROTEINS on RIBOSOMES, directed by MESSENGER RNA, via TRANSFER RNA that is charged with standard proteinogenic AMINO ACIDS.CRADD Signaling Adaptor Protein: 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.Tumor Cells, Cultured: 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.bcl-X Protein: 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.Protein Binding: 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.Ribosomes: Multicomponent ribonucleoprotein structures found in the CYTOPLASM of all cells, and in MITOCHONDRIA, and PLASTIDS. They function in PROTEIN BIOSYNTHESIS via GENETIC TRANSLATION.Bacterial Proteins: Proteins found in any species of bacterium.Viral Proteins: Proteins found in any species of virus.Cell Line, Tumor: A cell line derived from cultured tumor cells.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.Cell Survival: 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.Anticodon: The sequential set of three nucleotides in TRANSFER RNA that interacts with its complement in MESSENGER RNA, the CODON, during translation in the ribosome.Staurosporine: 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, Messenger: 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.Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes.Fas Ligand Protein: 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.RNA, Transfer, Amino Acyl: 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.In Situ Nick-End Labeling: 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, Cultured: 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.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Methionine-tRNA Ligase: An enzyme that activates methionine with its specific transfer RNA. EC 6.1.1.10.Transfection: 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.Blotting, Western: 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.Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.TNF-Related Apoptosis-Inducing Ligand: 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.Annexin A5: A protein of the annexin family isolated from human PLACENTA and other tissues. It inhibits cytosolic PHOSPHOLIPASE A2, and displays anticoagulant activity.Prokaryotic Initiation Factor-3: 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.Apoptosis Inducing Factor: 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.Codon: 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).N-Formylmethionine: 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.Calpain: 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 3.4.22.4.HL-60 Cells: 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)DNA: 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).Cloning, Molecular: 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.Benzoyl Peroxide: 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.Caspase 12: 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.Protein Structure, Tertiary: 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.Membrane Potential, Mitochondrial: 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.Necrosis: 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.Serpins: 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.Models, Biological: 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.Trans-Activators: Diffusible gene products that act on homologous or heterologous molecules of viral or cellular DNA to regulate the expression of proteins.Thromboplastin: 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.Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.Methionine: A sulfur-containing essential L-amino acid that is important in many body functions.Kinetics: The rate dynamics in chemical or physical systems.Tumor Necrosis Factor-alpha: 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.Mitochondrial Proteins: Proteins encoded by the mitochondrial genome or proteins encoded by the nuclear genome that are imported to and resident in the MITOCHONDRIA.Oligoribonucleotides: 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.Time Factors: Elements of limited time intervals, contributing to particular results or situations.bcl-2 Homologous Antagonist-Killer Protein: 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.Sequence Homology, Amino Acid: The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer.Cell-Free System: 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)Drosophila Proteins: 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.Transcription Factor TFIID: 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.Death Domain Receptor Signaling Adaptor Proteins: 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.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water.Receptors, Death Domain: 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.Mutagenesis, Site-Directed: Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.Origin Recognition Complex: The origin recognition complex is a multi-subunit DNA-binding protein that initiates DNA REPLICATION in eukaryotes.Cocarcinogenesis: The combination of two or more different factors in the production of cancer.Gene Expression Regulation: 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.Cytosol: Intracellular fluid from the cytoplasm after removal of ORGANELLES and other insoluble cytoplasmic components.Reactive Oxygen Species: 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.Cell Nucleus: 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)Protein Processing, Post-Translational: 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-2: 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 Fusion Proteins: 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.DNA Primers: 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.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.Granzymes: 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.Proto-Oncogene Proteins: 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.Saccharomyces cerevisiae: 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, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Cascara: Dried aged bark of a buckthorn, Frangula purshiana (FRANGULA), that contains the anthraquinone EMODIN and cascarosides. It is used as a laxative (CATHARTICS).Etoposide: 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.Eukaryotic Initiation Factor-1: 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.Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells.Intracellular Signaling Peptides and Proteins: 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.Tumor Suppressor Protein p53: 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.Replicon: 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)ToluidinesSequence Homology, Nucleic Acid: 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.Drosophila: 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.DNA, Bacterial: Deoxyribonucleic acid that makes up the genetic material of bacteria.Peptide Chain Elongation, Translational: A process of GENETIC TRANSLATION, when an amino acid is transferred from its cognate TRANSFER RNA to the lengthening chain of PEPTIDES.Flow Cytometry: 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.Sequence Alignment: 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.Receptors, Tumor Necrosis Factor: Cell surface receptors that bind TUMOR NECROSIS FACTORS and trigger changes which influence the behavior of cells.Caspase 14: A short pro-domain caspase that is almost exclusively expressed in the EPIDERMIS and may play a role in the differentiation of epidermal KERATINOCYTES.Restriction Mapping: Use of restriction endonucleases to analyze and generate a physical map of genomes, genes, or other segments of DNA.Gene Expression Regulation, Enzymologic: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in enzyme synthesis.Receptors, TNF-Related Apoptosis-Inducing Ligand: 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.Mice, Inbred C57BLCASP8 and FADD-Like Apoptosis Regulating Protein: 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.Papilloma: 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)Immunoblotting: 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.DNA Footprinting: 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)NF-kappa B: 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.Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane.Serine Endopeptidases: Any member of the group of ENDOPEPTIDASES containing at the active site a serine residue involved in catalysis.Down-Regulation: 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, Fluorescence: 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.Nuclear Proteins: 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.Genes, bcl-2: 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.Cell Proliferation: All of the processes involved in increasing CELL NUMBER including CELL DIVISION.Polymerization: Chemical reaction in which monomeric components are combined to form POLYMERS (e.g., POLYMETHYLMETHACRYLATE).Cell Cycle: 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.Phosphatidylserines: 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.Photoinitiators, Dental: 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.JNK Mitogen-Activated Protein Kinases: 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.Methylmethacrylate: The methyl ester of methacrylic acid. It polymerizes easily to form POLYMETHYL METHACRYLATE. It is used as a bone cement.Receptor-Interacting Protein Serine-Threonine Kinases: 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.Membrane Proteins: 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.Methylmethacrylates: The methyl esters of methacrylic acid that polymerize easily and are used as tissue cements, dental materials, and absorbent for biological substances.Mice, Knockout: 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.Structure-Activity Relationship: 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.Adaptor Proteins, Signal Transducing: 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 enzymesAmidinesRNA, Small Interfering: 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.Mitochondrial Membranes: 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).Lamins: Nuclear matrix proteins that are structural components of the NUCLEAR LAMINA. They are found in most multicellular organisms.Adenosine Triphosphate: 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.Neoplasm Proteins: 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.Alanine-tRNA Ligase: An enzyme that activates alanine with its specific transfer RNA. EC 6.1.1.7.Carcinogens: 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.Ultraviolet Rays: 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.Polymethyl Methacrylate: 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.Coumarins: Synthetic or naturally occurring substances related to coumarin, the delta-lactone of coumarinic acid.Intracellular Membranes: 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.Oligonucleotides: 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)U937 Cells: 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.Neurons: 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.RNA, Transfer, Amino Acid-Specific: 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.Bovine papillomavirus 1: A species of DELTAPAPILLOMAVIRUS infecting cattle.Drosophila melanogaster: A species of fruit fly much used in genetics because of the large size of its chromosomes.Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.

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
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
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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
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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 ...
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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 ...
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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.
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 ...
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
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
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. ...
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 ...
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). ...
... 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 ... Caspase-independent apoptosis[edit]. The characterization of the caspases allowed the development of caspase inhibitors, which ...
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 ... that may direct the destruction of keratinocytes through apoptosis by activating caspase. As a result of increased exposure to ...
... 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 ... 2002). "Caspase-8 and Apaf-1-independent Caspase-9 Activation in Sendai Virus-infected Cells". The Journal of Biological ... This functional apoptosome then can provide a platform activation of caspase 9. Caspase 9 exists as a zymogen in the cytosol ...
... 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 are 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 XAIP binds to ... This is unexpected because in nerve growth factor withdrawal, caspase-3 and -9 are activated, causing cell death, which are the ...
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 ...
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 ...
... 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 3.4.22.61), caspase-9 (EC 3.4.22.62) and caspase-10 (EC 3.4.22.63). ... Caspase-2 (EC 3.4.22.55, ICH-1, NEDD-2, caspase-2L, caspase-2S, neural precursor cell expressed developmentally down-regulated ... Caspase-2 at the US National Library of Medicine Medical Subject Headings (MeSH) Molecular and Cellular Biology portal. ... Mancini, M.; Machamer, C.E.; Roy, S.; Nicholson, D.W.; Thornberry, N.A.; Casciola-Rosen, L.A.; Rosen, A. (2000). "Caspase-2 is ...
Gly Caspase-10 is an initiator caspase, as are caspase-2 (EC 3.4.22.55), caspase-8 (EC 3.4.22.61) and caspase-9 (EC 3.4.22.62 ... Shikama, Y.; Yamada, M.; Miyashita, T. (2003). "Caspase-8 and caspase-10 activate NF-κB through RIP, NIK and IKKα kinases". Eur ... Fischer, U.; Stroh, C.; Schulze-Osthoff, K. (2006). "Unique and overlapping substrate specificities of caspase-8 and caspase-10 ... Caspase-10 (EC 3.4.22.63, 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 ...
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". J Biol Chem. 277 (28): 25617-23. doi:10.1074/jbc.M202285200. PMID 11980907. Marshall KR ...
"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 ...
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 ...
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 ...
... 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 ...
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 ...
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 (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 ...
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 ...
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. ...
... 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 ...
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 ...
... 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, ...
... 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 ...
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 ...
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, ...
... 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), ...
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 ...
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 ...
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 ...
activate caspase. extrinsic: death ligand + death receptor allows caspases to be brought close ... able to cleave aspartic acid residues (cysteine-aspartic acid-proteases). initiators activate effectors. ... intrinsic & extrinsic path converge: caspase activation. caspase -> proteolytic enzymes that destroy cell components. contain ...
Chen M, Wang J (2002) Initiator caspases in apoptosis signaling pathways. Apoptosis 7:313-319CrossRefPubMedGoogle Scholar ...
Novel initiator caspase reporters uncover unknown features of caspase-activating cells. Luis Alberto Baena-Lopez, Lewis ...
  • 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)
  • Binding of Fas to its ligand or agonistic antibody induces the recruitment and autoactivation of initiator procaspase-8 ( Krammer, 2000 ). (rupress.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)
  • 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)
  • 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)