A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 9. Isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.
A 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.
Endogenous and exogenous compounds and that either inhibit CASPASES or prevent their activation.
A long pro-domain caspase that contains a caspase recruitment domain in its pro-domain region. Caspase 9 is activated during cell stress by mitochondria-derived proapoptotic factors and by CARD SIGNALING ADAPTOR PROTEINS such as APOPTOTIC PROTEASE-ACTIVATING FACTOR 1. It activates APOPTOSIS by cleaving and activating EFFECTOR CASPASES.
A 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.
A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 3 and CASPASE 10. Several isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.
A 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.
A RIP serine-theonine kinase that contains a C-terminal caspase activation and recruitment domain. It can signal by associating with other CARD-signaling adaptor proteins and INITIATOR CASPASES that contain CARD domains within their N-terminal pro-domain region.
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.
One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.
A 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.
Inhibitors of SERINE ENDOPEPTIDASES and sulfhydryl group-containing enzymes. They act as alkylating agents and are known to interfere in the translation process.
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.
Exogenous and endogenous compounds which inhibit CYSTEINE ENDOPEPTIDASES.
A 34 kDa signal transducing adaptor protein that associates with TUMOR NECROSIS FACTOR RECEPTOR TYPE 1. It facilitates the recruitment of signaling proteins such as TNF RECEPTOR-ASSOCIATED FACTOR 2 and FAS ASSOCIATED DEATH DOMAIN PROTEIN to the receptor complex.
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.
A short pro-domain caspase that is almost exclusively expressed in the EPIDERMIS and may play a role in the differentiation of epidermal KERATINOCYTES.
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.
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.
Congenital structural abnormalities of the skin.
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.
A tumor necrosis factor receptor subtype that has specificity for TUMOR NECROSIS FACTOR ALPHA and LYMPHOTOXIN ALPHA. It is constitutively expressed in most tissues and is a key mediator of tumor necrosis factor signaling in the vast majority of cells. The activated receptor signals via a conserved death domain that associates with specific TNF RECEPTOR-ASSOCIATED FACTORS in the CYTOPLASM.
Splitting the DNA into shorter pieces by endonucleolytic DNA CLEAVAGE at multiple sites. It includes the internucleosomal DNA fragmentation, which along with chromatin condensation, are considered to be the hallmarks of APOPTOSIS.
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.
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.
A NOD signaling adaptor protein that contains two C-terminal leucine-rich domains which recognize bacterial PEPTIDOGLYCAN. It signals via an N-terminal capase recruitment domain that interacts with other CARD SIGNALING ADAPTOR PROTEINS such as RIP SERINE-THEONINE KINASES. The protein plays a role in the host defense response by signaling the activation of CASPASES and the MAP KINASE SIGNALING SYSTEM. Mutations of the gene encoding the nucleotide oligomerization domain 2 protein have been associated with increased susceptibility to CROHN DISEASE.
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.
Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed)
A 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.
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)
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.
Established cell cultures that have the potential to propagate indefinitely.
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.
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.
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.
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.
A member of the Bcl-2 protein family and homologous partner of C-BCL-2 PROTO-ONCOGENE PROTEIN. It regulates the release of CYTOCHROME C and APOPTOSIS INDUCING FACTOR from the MITOCHONDRIA. Several isoforms of BCL2-associated X protein occur due to ALTERNATIVE SPLICING of the mRNA for this protein.
A cell line derived from cultured tumor cells.
A group of enzymes that catalyzes the transfer of a phosphate group onto a phosphate group acceptor. EC 2.7.4.
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.
The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability.
An abnormal triangular fold of membrane in the interpalpebral fissure, extending from the conjunctiva to the cornea, being immovably united to the cornea at its apex, firmly attached to the sclera throughout its middle portion, and merged with the conjunctiva at its base. (Dorland, 27th ed)
A NOD-signaling adaptor protein that contains a C-terminal leucine-rich domain which recognizes bacterial PEPTIDOGLYCAN. It signals via an N-terminal caspase recruitment domain that interacts with other CARD SIGNALING ADAPTOR PROTEINS such as RIP SERINE-THEONINE KINASES. It plays a role in the host defense response by signaling the activation of CASPASES and the MAP KINASE SIGNALING SYSTEM.
A CELL LINE derived from human T-CELL LEUKEMIA and used to determine the mechanism of differential susceptibility to anti-cancer drugs and radiation.
Cleavage of proteins into smaller peptides or amino acids either by PROTEASES or non-enzymatically (e.g., Hydrolysis). It does not include Protein Processing, Post-Translational.
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.
Transport proteins that carry specific substances in the blood or across cell membranes.
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.
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.
Infections with bacteria of the family BACTEROIDACEAE.
Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
A member of the Bcl-2 protein family that reversibly binds MEMBRANES. It is a pro-apoptotic protein that is activated by caspase cleavage.
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.
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.
Small double-stranded, non-protein coding RNAs (21-31 nucleotides) involved in GENE SILENCING functions, especially RNA INTERFERENCE (RNAi). Endogenously, siRNAs are generated from dsRNAs (RNA, DOUBLE-STRANDED) by the same ribonuclease, Dicer, that generates miRNAs (MICRORNAS). The perfect match of the siRNAs' antisense strand to their target RNAs mediates RNAi by siRNA-guided RNA cleavage. siRNAs fall into different classes including trans-acting siRNA (tasiRNA), repeat-associated RNA (rasiRNA), small-scan RNA (scnRNA), and Piwi protein-interacting RNA (piRNA) and have different specific gene silencing functions.
The artificial induction of GENE SILENCING by the use of RNA INTERFERENCE to reduce the expression of a specific gene. It includes the use of DOUBLE-STRANDED RNA, such as SMALL INTERFERING RNA and RNA containing HAIRPIN LOOP SEQUENCE, and ANTI-SENSE OLIGONUCLEOTIDES.
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.
An LDL-receptor related protein that combines with cell surface FRIZZLED RECEPTORS to form WNT PROTEIN-binding receptors. The protein plays an important role in the WNT SIGNALING PATHWAY during EMBRYONIC DEVELOPMENT and in regulation of vascular cell proliferation.
Peptides composed of between two and twelve amino acids.
A Wnt protein subtype that plays a role in cell-cell signaling during EMBRYONIC DEVELOPMENT and the morphogenesis of the developing NEURAL TUBE.
Arrest of cell locomotion or cell division when two cells come into contact.
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.
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.
Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.
Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
Complexing agent for removal of traces of heavy metal ions. It acts also as a hypocalcemic agent.
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.
A signal transducing tumor necrosis factor receptor associated factor that is involved in TNF RECEPTOR feedback regulation. It is similar in structure and appears to work in conjunction with TNF RECEPTOR-ASSOCIATED FACTOR 1 to inhibit APOPTOSIS.
A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors.
A gene silencing phenomenon whereby specific dsRNAs (RNA, DOUBLE-STRANDED) trigger the degradation of homologous mRNA (RNA, MESSENGER). The specific dsRNAs are processed into SMALL INTERFERING RNA (siRNA) which serves as a guide for cleavage of the homologous mRNA in the RNA-INDUCED SILENCING COMPLEX. DNA METHYLATION may also be triggered during this process.
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.
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.
Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.
A broad category of carrier proteins that play a role in SIGNAL TRANSDUCTION. They generally contain several modular domains, each of which having its own binding activity, and act by forming complexes with other intracellular-signaling molecules. Signal-transducing adaptor proteins lack enzyme activity, however their activity can be modulated by other signal-transducing enzymes
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.
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)
Human colonic ADENOCARCINOMA cells that are able to express differentiation features characteristic of mature intestinal cells such as the GOBLET CELLS.
A protein of the annexin family isolated from human PLACENTA and other tissues. It inhibits cytosolic PHOSPHOLIPASE A2, and displays anticoagulant activity.
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.
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)
Physiologically inactive substances that can be converted to active enzymes.
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.
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.
A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.
A species of gram-negative, anaerobic, rod-shaped bacteria originally classified within the BACTEROIDES genus. This bacterium produces a cell-bound, oxygen-sensitive collagenase and is isolated from the human mouth.
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.
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.
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.
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.
A complex signaling pathway whose name is derived from the DROSOPHILA Wg gene, which when mutated results in the wingless phenotype, and the vertebrate INT gene, which is located near integration sites of MOUSE MAMMARY TUMOR VIRUS. The signaling pathway is initiated by the binding of WNT PROTEINS to cells surface WNT RECEPTORS which interact with the AXIN SIGNALING COMPLEX and an array of second messengers that influence the actions of BETA CATENIN.
Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.
Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.
Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.
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.
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.
Substances that inhibit or prevent the proliferation of NEOPLASMS.
Intracellular signaling adaptor proteins that bind to the cytoplasmic death domain region found on DEATH DOMAIN RECEPTORS. Many of the proteins in this class take part in intracellular signaling from TUMOR NECROSIS FACTOR RECEPTORS.
The relationship between the dose of an administered drug and the response of the organism to the drug.
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.
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.
A family of intracellular signaling adaptor proteins that contain caspase activation and recruitment domains. Proteins that contain this domain play a role in APOPTOSIS-related signal transduction by associating with other CARD domain-containing members and in activating INITIATOR CASPASES that contain CARD domains within their N-terminal pro-domain region.
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.
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.
Elements of limited time intervals, contributing to particular results or situations.
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.
Proteins encoded by the mitochondrial genome or proteins encoded by the nuclear genome that are imported to and resident in the MITOCHONDRIA.
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.
Agents obtained from higher plants that have demonstrable cytostatic or antineoplastic activity.
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.
Cell surface receptors that bind TUMOR NECROSIS FACTORS and trigger changes which influence the behavior of cells.
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.
All of the processes involved in increasing CELL NUMBER including CELL DIVISION.
Glycoproteins found on the membrane or surface of cells.
Intracellular fluid from the cytoplasm after removal of ORGANELLES and other insoluble cytoplasmic components.
A pro-apoptotic protein and member of the Bcl-2 protein family that is regulated by PHOSPHORYLATION. Unphosphorylated Bad protein inhibits the activity of BCL-XL PROTEIN.
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.
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.
A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.
A human cell line established from a diffuse histiocytic lymphoma (HISTIOCYTIC LYMPHOMA, DIFFUSE) and displaying many monocytic characteristics. It serves as an in vitro model for MONOCYTE and MACROPHAGE differentiation.
The 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.
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).
Proteins prepared by recombinant DNA technology.
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.
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.
Members of the class of neutral glycosphingolipids. They are the basic units of SPHINGOLIPIDS. They are sphingoids attached via their amino groups to a long chain fatty acyl group. They abnormally accumulate in FABRY DISEASE.
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.
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.
The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.
The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds.
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.
The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.
A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols.
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.
Compounds which inhibit the synthesis of proteins. They are usually ANTI-BACTERIAL AGENTS or toxins. Mechanism of the action of inhibition includes the interruption of peptide-chain elongation, the blocking the A site of ribosomes, the misreading of the genetic code or the prevention of the attachment of oligosaccharide side chains to glycoproteins.
The action of a drug in promoting or enhancing the effectiveness of another drug.
A member of the myeloid leukemia factor (MLF) protein family with multiple alternatively spliced transcript variants encoding different protein isoforms. In hematopoietic cells, it is located mainly in the nucleus, and in non-hematopoietic cells, primarily in the cytoplasm with a punctate nuclear localization. MLF1 plays a role in cell cycle differentiation.
A positive 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.
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.
A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.
The voltage differences across a membrane. For cellular membranes they are computed by subtracting the voltage measured outside the membrane from the voltage measured inside the membrane. They result from differences of inside versus outside concentration of potassium, sodium, chloride, and other ions across cells' or ORGANELLES membranes. For excitable cells, the resting membrane potentials range between -30 and -100 millivolts. Physical, chemical, or electrical stimuli can make a membrane potential more negative (hyperpolarization), or less negative (depolarization).
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)
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.
The segregation and degradation of damaged or unwanted cytoplasmic constituents by autophagic vacuoles (cytolysosomes) composed of LYSOSOMES containing cellular components in the process of digestion; it plays an important role in BIOLOGICAL METAMORPHOSIS of amphibians, in the removal of bone by osteoclasts, and in the degradation of normal cell components in nutritional deficiency states.
Synthetic or naturally occurring substances related to coumarin, the delta-lactone of coumarinic acid.
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.
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.
A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi).
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.
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.
Histochemical localization of immunoreactive substances using labeled antibodies as reagents.
A superfamily of PROTEIN-SERINE-THREONINE KINASES that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by MITOGEN-ACTIVATED PROTEIN KINASE KINASES, which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP KINASE KINASE KINASES).
Quaternary ammonium analog of ethidium; an intercalating dye with a specific affinity to certain forms of DNA and, used as diiodide, to separate them in density gradients; also forms fluorescent complexes with cholinesterase which it inhibits.
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.
A protein-serine-threonine kinase that is activated by PHOSPHORYLATION in response to GROWTH FACTORS or INSULIN. It plays a major role in cell metabolism, growth, and survival as a core component of SIGNAL TRANSDUCTION. Three isoforms have been described in mammalian cells.
Antibiotic substance isolated from streptomycin-producing strains of Streptomyces griseus. It acts by inhibiting elongation during protein synthesis.
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.
A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.
Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES).
Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals.
Compounds that inhibit cell production of DNA or RNA.
A mitogen-activated protein kinase subfamily that regulates a variety of cellular processes including CELL GROWTH PROCESSES; CELL DIFFERENTIATION; APOPTOSIS; and cellular responses to INFLAMMATION. The P38 MAP kinases are regulated by CYTOKINE RECEPTORS and can be activated in response to bacterial pathogens.
The process of moving proteins from one cellular compartment (including extracellular) to another by various sorting and transport mechanisms such as gated transport, protein translocation, and vesicular transport.
Any member of the group of ENDOPEPTIDASES containing at the active site a serine residue involved in catalysis.
Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.
Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS.
The N-acetyl derivative of CYSTEINE. It is used as a mucolytic agent to reduce the viscosity of mucous secretions. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates.
A large multisubunit complex that plays an important role in the degradation of most of the cytosolic and nuclear proteins in eukaryotic cells. It contains a 700-kDa catalytic sub-complex and two 700-kDa regulatory sub-complexes. The complex digests ubiquitinated proteins and protein activated via ornithine decarboxylase antizyme.
Proteins found in any species of virus.
The process of cleaving a chemical compound by the addition of a molecule of water.
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)
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.
A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials.
Resistance or diminished response of a neoplasm to an antineoplastic agent in humans, animals, or cell or tissue cultures.
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.
Preparations of cell constituents or subcellular materials, isolates, or substances.
The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.
Various physiological or molecular disturbances that impair ENDOPLASMIC RETICULUM function. It triggers many responses, including UNFOLDED PROTEIN RESPONSE, which may lead to APOPTOSIS; and AUTOPHAGY.
Cells that line the inner and outer surfaces of the body by forming cellular layers (EPITHELIUM) or masses. Epithelial cells lining the SKIN; the MOUTH; the NOSE; and the ANAL CANAL derive from ectoderm; those lining the RESPIRATORY SYSTEM and the DIGESTIVE SYSTEM derive from endoderm; others (CARDIOVASCULAR SYSTEM and LYMPHATIC SYSTEM) derive from mesoderm. Epithelial cells can be classified mainly by cell shape and function into squamous, glandular and transitional epithelial cells.
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.
A light microscopic technique in which only a small spot is illuminated and observed at a time. An image is constructed through point-by-point scanning of the field in this manner. Light sources may be conventional or laser, and fluorescence or transmitted observations are possible.
Adenine nucleotides which contain deoxyribose as the sugar moiety.
The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.
Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids.
Eukaryotic cell line obtained in a quiescent or stationary phase which undergoes conversion to a state of unregulated growth in culture, resembling an in vitro tumor. It occurs spontaneously or through interaction with viruses, oncogenes, radiation, or drugs/chemicals.
Nuclear matrix proteins that are structural components of the NUCLEAR LAMINA. They are found in most multicellular organisms.
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.
The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in neoplastic tissue.
Proteins found in any species of insect.
High molecular weight proteins found in the MICROTUBULES of the cytoskeletal system. Under certain conditions they are required for TUBULIN assembly into the microtubules and stabilize the assembled microtubules.
The part of a cell that contains the CYTOSOL and small structures excluding the CELL NUCLEUS; MITOCHONDRIA; and large VACUOLES. (Glick, Glossary of Biochemistry and Molecular Biology, 1990)
Property of membranes and other structures to permit passage of light, heat, gases, liquids, metabolites, and mineral ions.
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.
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.
An interleukin-1 subtype that is synthesized as an inactive membrane-bound pro-protein. Proteolytic processing of the precursor form by CASPASE 1 results in release of the active form of interleukin-1beta from the membrane.
A lysosomal cysteine proteinase with a specificity similar to that of PAPAIN. The enzyme is present in a variety of tissues and is important in many physiological and pathological processes. In pathology, cathepsin B has been found to be involved in DEMYELINATION; EMPHYSEMA; RHEUMATOID ARTHRITIS, and NEOPLASM INVASIVENESS.
Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.
An antibiotic produced by Pseudomonas cocovenenans. It is an inhibitor of MITOCHONDRIAL ADP, ATP TRANSLOCASES. Specifically, it blocks adenine nucleotide efflux from mitochondria by enhancing membrane binding.
"RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3". Cell. 157 (5): 1189-202. doi:10.1016/j.cell.2014.04. ...
... initiating the caspase cascade. The activated caspases can go on to cleave intracellular proteins such as inhibitor of caspase- ... FADD also plays a role in regulating necroptosis, a process requiring the serine/threonine kinases, RIPK1 and RIPK3. Activated ... "Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8". Journal of ... Since activation of caspase 8 requires FADD in order to bring the procaspase 8 molecules into close proximity to one another to ...
... the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis. Recent studies ... 8 (3): 197-204. doi:10.1007/s10456-005-9010-0. PMID 16328160. Mercurio, Arthur M; Bachelder, Robin E; Bates, Richard C; Chung, ... STAT3 and RANTES contribute to the maintenance of drug resistance by upregulating anti-apoptotic signals and inhibiting caspase ...
... the RIPK1 and RIPK3 are phosphorylated and lead to deterioration of the cell in the absence of caspase activation. The ... The caspase-independence of necroptosis allows the cell to bypass caspase activation, decreasing the time during which the ... which in turn recruits RIPK1. In the absence of active Caspase 8, RIPK1 and RIPK3 auto- and transphosphorylate each other, ... in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to ...
"Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis". Nature. 574 (7778): 428-431. doi:10.1038/ ... caspase-11 or caspase-5 in humans, which is responsible for some of the effects that had been attributed to caspase-1, ... The 2011 paper showed that mice lacking the gene that encodes caspase-1 also carry a mutation in a neighboring caspase gene, ... Dixit was among the first scientists to demonstrate that other immune caspases besides death caspases are incorporated into the ...
... as well as apoptosis via RIPK1 and caspase 8. These distressed cells then excrete alarmins, proteases, and damage-associated ... Cells undergo cell death via three main mechanisms: nectoptosis via RIPK1, FADD, RIPK3, and MLKL, ferroptosis via GPX4 ...
Kanneganti's lab showed compensatory roles for NLRP3/caspase-1 and caspase-8 in the regulation of IL-1β production in ... She identified the role of the IL-1α and RIPK1/TAK1/SYK signaling pathway in skin inflammation. Furthermore, her studies also ... Her lab identified caspase-8 and FADD as expression and activation regulators of both the canonical and non-canonical NLRP3 ... This finding went against the dogma that existed at that time that caspase-8 and FADD were involved only in the apoptotic ...
Caspase inhibition within this complex allows RIPK1 and RIPK3 to autotransphosphorylate each other, forming another complex ... RIPK1 is an enzyme that in humans is encoded by the RIPK1 gene, which is located on chromosome 6. This protein belongs to the ... Although, RIPK1 has been primarily studied in the context of TNFR signaling, RIPK1 is also activated in response to diverse ... Also, proteolytic processing of RIPk1, through both caspase-dependent and -independent mechanisms, triggers lethality that is ...
Caspase-10, Caspase-2, Caspase-3, Caspase-6, Caspase-7, Caspase-9, DEDD, FADD, FasL, FasR, IFT57, NOL3, PEA15, RIPK1, TNFRSF10B ... Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive ... Cowling V, Downward J (October 2002). "Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis ... Biochemically, caspase-8 was found to enter the complex of the inhibitor of NF-κB kinase (IKK) with the upstream Bcl10-MALT1 ( ...
... the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis.[12] ... STAT3 and RANTES contribute to the maintenance of drug resistance by upregulating anti-apoptotic signals and inhibiting caspase ... 8] Evidence shows that autocrine VEGF is involved in two major aspects of invasive carcinoma: survival and migration. Moreover ...
Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive ... Cowling V, Downward J (October 2002). "Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis ... "Entrez Gene: CASP8 caspase 8, apoptosis-related cysteine peptidase".. *^ a b c Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, ... Caspase 3. Pro-apoptotic:. BAX. BAK1/Bcl-2 homologous antagonist killer. Bcl-2-associated death promoter. Anti-apoptotic:. Bcl- ...
"Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions". The Journal of Cell ... Her group then identified RIPK1 as the target for necrostatin-1, thus implicating it as a key player in necroptosis. Yuan went ... and her discovery of caspase-11's role in regulating caspase-1-driven inflammation. In 2005, Yuan's group discovered a non- ... As of 2019[update], small-molecule inhibitors of RIPK1 have advanced beyond Phase I human clinical trials for the treatment of ...
1998). "The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases". EMBO J. 16 (23): 6914-25. doi:10.1093/ ... Baculoviral IAP repeat-containing protein 3 has been shown to interact with: CASP9, RIPK1, TRAF1, TRAF2, and UBE2D2. GRCh38: ... cIAP2 is a member of the inhibitor of apoptosis family that inhibit apoptosis by interfering with the activation of caspases. ... 1998). "IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases". EMBO J. ...
cIAP1 is a member of the Inhibitor of Apoptosis family that inhibit apoptosis by interfering with the activation of caspases. ... BIRC2 has been shown to interact with: CASP9, DIABLO, GSPT1, HSP90B1, HTRA2, RIPK1, RIPK2 TNFSF14, TRAF1, TRAF2, and UBC. ... "The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases". EMBO J. 16 (23): 6914-25. doi:10.1093/emboj/16.23 ... "The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases". EMBO J. 16 (23): 6914-25. doi:10.1093/emboj/16.23 ...
Shu HB, Halpin DR, Goeddel DV (June 1997). "Casper is a FADD- and caspase-related inducer of apoptosis". Immunity. 6 (6): 751- ... RIPK1, SPHK1, TANK, TANK-binding kinase 1, TNFAIP3, TNFRSF13B, TNFRSF14, TNFRSF1A, TNFRSF1B, TNFSF14, TRADD, TRAF interacting ... "The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways". Curr. Biol. 10 (11): 640-8. doi: ... "The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases". EMBO J. 16 (23): 6914-25. doi:10.1093/emboj/16.23 ...
RIPK1/RIP kinase, and numbers of other CARD domain-containing proteins. CRADD has been shown to interact with RIPK1 and Caspase ... "Solution structure of the RAIDD CARD and model for CARD/CARD interaction in caspase-2 and caspase-9 recruitment". Cell. 94 (2 ... "Identification of a caspase-2 isoform that behaves as an endogenous inhibitor of the caspase cascade". Cancer Res. 60 (24): ... "Identification of a caspase-2 isoform that behaves as an endogenous inhibitor of the caspase cascade". Cancer Res. 60 (24): ...
However, the involvement of RIPK1 has not been observed, suggesting that this necrosis is accidental in nature and not ... Instead, several hallmarks of necrosis are observed, such as caspase-independent cell death, the loss of plasma membrane ... Clinical Cancer Research, 17(8), 2484-2492. Sachs, C. W., Safa, A. R., Harrison, S. D., & Fine, R. L. (1995). Partial ...
Chaudhary PM, Eby MT, Jasmin A, Kumar A, Liu L, Hood L (2000). "Activation of the NF-kappaB pathway by caspase 8 and its ... TNFRSF1A has been shown to interact with: BAG4, CASP10, FADD, IKK2, JAK1, JAK2, PIP4K2B, PSMD2, RIPK1, SUMO1, TRADD TRAF2, ... 13 (1): 13-8. PMID 11801527. Castellino AM, Parker GJ, Boronenkov IV, Anderson RA, Chao MV (1997). "A novel interaction between ... 22 (8): 2536-43. doi:10.1128/MCB.22.8.2536-2543.2002. PMC 133739. PMID 11909948. Gajate C, Mollinedo F (2005). "Cytoskeleton- ...
Costanzo A, Guiet C, Vito P (1999). "c-E10 is a caspase-recruiting domain-containing protein that interacts with components of ... TRADD has been shown to interact with: FADD, Keratin 18 RIPK1, STAT1, TNFRSF1A, TNFRSF25, and TRAF2. TRAF RIP GRCh38: Ensembl ... 162 (2): 1042-8. PMID 9916731. Schütze S, Machleidt T, Adam D, Schwandner R, Wiegmann K, Kruse ML, Heinrich M, Wickel M, Krönke ... 277 (37): 34343-8. doi:10.1074/jbc.M204169200. PMID 12107169. Inada H, Izawa I, Nishizawa M, Fujita E, Kiyono T, Takahashi T, ...
Bakulovirusni protein 3 koji sadrži IAP ponavljanje formira interakcije sa TRAF1,[4][5] TRAF2,[4][5][6][7] RIPK1,[8] kaspazom-9 ... "IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases". EMBO J. 17 (8): ... functions as a ubiquitin-protein ligase and promotes in vitro monoubiquitination of caspases 3 and 7". J. Biol. Chem. 275 (35 ... "IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases". EMBO J. (ENGLAND ...
... the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis. Recent studies ... 8 (3): 197-204. doi:10.1007/s10456-005-9010-0. PMID 16328160. Mercurio, Arthur M; Bachelder, Robin E; Bates, Richard C; Chung, ... STAT3 and RANTES contribute to the maintenance of drug resistance by upregulating anti-apoptotic signals and inhibiting caspase ...
5: Entinostat enhances apoptosis in response to IAP antagonists via Ku70, RIPK1 and caspase-8.. From: Cytoplasmic FLIP(S) and ... Western blot analysis of RIPK1 and β-actin in PC3 cells treated with 10 nM SC or RIPK1 siRNA. d Annexin-V/PI flow cytometry ( ... 5: Entinostat enhances apoptosis in response to IAP antagonists via Ku70, RIPK1 and caspase-8. , Cell Death & Disease ... c Annexin-V/PI flow cytometry analysis of PC3 cells transfected for 24 h with 20 nM scrambled control (SC) or RIPK1 siRNA ...
... in contrast to RIPK1-dependent apoptosis downstream of TNFR1, we did not find Ripk1 associated with caspase-8 in a death- ... We found that Ripk1-deficient MEFs are protected from apoptosis induced by ER stressors, which is reflected by reduced caspase ... Ripk1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved er stress conditions. ... Our data rather suggest that RIPK1 indirectly regulates caspase-8 activation, in part via interaction with the ER stress sensor ...
RIPK1 is shown to have a crucial role-independent of its known kinase function-in suppressing epithelial cell apoptosis and ... RIPK1 and Caspase-8 Ensure Chromosome Stability Independently of Their Role in Cell Death and Inflammation *Gianmaria Liccardi ... Intestinal pathology in Ripk1−/− and RIPK1IEC-KO mice.. *2.. Mild intestinal inflammation in RIPK1IEC-KO mice.. *3.. Assessment ... A.P. performed the gene targeting in embryonic stem cells and generated the Ripk1fl/fl, Ripk1D138N/D138N and Triffl/fl mice. M. ...
... Academic Article * ... Here, we report an unanticipated cell-death- and inflammation-independent function of RIPK1 and Caspase-8, promoting faithful ... Genetic deletion and mitosis-specific inhibition of Ripk1 or Caspase-8 results in chromosome alignment defects independently of ... where PLK1s activity is controlled via RIPK1-dependent recruitment and Caspase-8-mediated cleavage. A fine balance of ...
Cycloheximide promotes caspase-8 activation by eliminating endogenous caspas … ... a RIPK1 K63 deubiquitinating enzyme. RIPK1 is critical for caspase-8 activation-induced by Smac mimetic but dispensable for ... RIPK1) from the activated TNF receptor complex to form a caspase-8-activating complex consisting of RIPK1, FADD, and caspase-8 ... TNF-alpha induces two distinct caspase-8 activation pathways Cell. 2008 May 16;133(4):693-703. doi: 10.1016/j.cell.2008.03.036 ...
Immunologists discover new RIPK1 mechanism that leads to cell death Scientists at St. Jude Childrens Research Hospital have ... Enzyme caspase-8 controls apoptosis, necroptosis and pyroptosis The enzyme caspase-8 induces a molecular cell death programme ... Study sheds light on complex caspase-1-induced cell death mechanisms Most unnecessary or dangerous cells such as virus-infected ... discovered a new way that the molecule RIPK1 leads to cell death in infected, damaged or unwanted cells showing that more than ...
... the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis. ...
RIPK1 is then deubiquitinated and dissociates, forming either complex IIa or IIb. Complex IIa is involved in caspase 8 ... RIPK1 recruits RIPK3 and they phosphorylate each other. This then leads to oligomerization and necrosome formation. ... For example, the vaccinia virus possesses inhibitors of both caspase 1 and 8, which are required for apoptosis, and therefore ... Complex IIb, however, is involved in necroptosis and is formed when caspase 8 is inhibited. ...
Activated RIPK1* then binds to FADD. In apoptosis-competent cells, the RIPK1*/FADD complex in turn binds to caspase-8 (complex ... p-S166 RIPK1, and RIPK1 antibodies in normal SDS/PAGE. (D) WT, Ripk1K584R/+, and Ripk1K584R/K584R immortalized MEFs were ... The Ripk1K584R mutation disrupts the formation of complex IIa. (A) WT, Ripk1K584R/+, and Ripk1K584R/K584R primary MEFs were ... Ripk1K584R/K584R mutant cells are resistant to necroptosis and RDA. (A) WT, Ripk1K584R/+, and Ripk1K584R/K584R immortalized ...
2017) RIPK1-dependent apoptosis bypasses pathogen blockade of innate signaling to promote immune defense. J Exp Med 214:3171- ... This death complex drives GsdmD cleavage and activation partially via caspase-1/11 and GsdmE cleavage via caspase-3 and caspase ... caspase-9, caspase-3, and caspase-7 have accumulated extracellularly by 5 h of LPS/5z7 stimulation (Fig. 2B). In contrast, ... 4A). In addition to the active p30 fragment generated by caspase-1 and caspase-11 as previously described (12, 36), we also ...
Caspase-8: not so silently deadly. Clin Transl Immunology 6(1)e124 (2017).. [http://dx.doi.org/10.1038/cti.2016.83] [PMID: ... Newton K. RIPK1 and RIPK3: critical regulators of inflammation and cell death. Trends Cell Biol 25(6): 347-53. (2015).. [http ... Kondylis V, Kumari S, Vlantis K, Pasparakis M. The interplay of IKK, NF-κB and RIPK1 signaling in the regulation of cell death ... RIPK1 mediates a disease-associated microglial response in Alzheimers disease. Proc Natl Acad Sci USA 114(41): E8788-97. (2017 ...
When cIAP1 and cIAP2 are depleted by SMAC mimetics, nonubiquitylated RIPK1 recruits caspase-8 to form an alternative complex, ... 2D and 4, C to E). IDN-6556, like Q-VD-OPh and Z-VAD-FMK, also inhibits the apoptotic caspase-3 and caspase-9 in vitro (fig. S7 ... 2A). Caspase inhibitors might sensitize cells to SMAC mimetics by inhibiting caspase-8 and promoting necroptotic cell death ( ... complex IIa, initiating apoptosis (12). In the presence of caspase inhibitors, a complex IIb is assembled, consisting of RIPK1 ...
Regulation of Cell Death by RIPK1 and Caspase-8. Kate Schroder, University of Queensland, Australia Myeloid Cell Identity ... Short Talk: Caspase-1 and Caspase-5 Are Differentially Activated by Extracellular Heme. ... The Role and Mechanism of RIPK1 in Cell Death and Neurodegeneration. Kevin M. Ryan, Beatson Institute for Cancer Research, UK ... Short Talk: A Forward Genetic Screen to Identify Mechanisms of Resistance to Caspase-Mediated Cell Death Induced by Pore- ...
"RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3". Cell. 157 (5): 1189-202. doi:10.1016/j.cell.2014.04. ...
Epub 2014 May 8. Research Support, Non-U.S. Govt ... RIPK1 also directly regulates caspase-8-mediated apoptosis or, ... Reduced inflammation in the Ripk1(-/-)Ripk3(-/-), Ripk1(-/-)Mlkl(-/-), and Ripk1(-/-)Myd88(-/-) mice prevented neonatal ... RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis.. Rickard JA1, ODonnell JA1, Evans JM2, ... Upon ligand binding, RIPK1 is recruited to tumor necrosis factor receptor superfamily (TNFRSF) and Toll-like receptor (TLR) ...
Caspase inhibition within this complex allows RIPK1 and RIPK3 to autotransphosphorylate each other, forming another complex ... RIPK1 is an enzyme that in humans is encoded by the RIPK1 gene, which is located on chromosome 6. This protein belongs to the ... Although, RIPK1 has been primarily studied in the context of TNFR signaling, RIPK1 is also activated in response to diverse ... Also, proteolytic processing of RIPk1, through both caspase-dependent and -independent mechanisms, triggers lethality that is ...
Unexpectedly, RIPK3 D161N promoted lethal RIPK1- and caspase-8-dependent apoptosis. In contrast, mice expressing RIPK1 D138N ... Cells expressing RIPK1 D138N were resistant to TNF-induced necroptosis, whereas TNF-induced signaling pathways promoting gene ... We engineered mice expressing catalytically inactive RIPK3 D161N or RIPK1 D138N to determine the need for the active kinase in ... Studies with RIPK3-deficient mice or the RIPK1 inhibitor necrostatin-1 suggest that necroptosis exacerbates pathology in many ...
Finally, we show that Bid impacts necroptotic signaling through modulation of caspase-8-mediated Ripk1 degradation. Thus, we ... Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice. Patrice N. Wagner, ... Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice. Blood, 133(2), 107- ... Genetically restoring Ripk1 to wild-type levels restores peripheral red cell counts as well as normal cytokine production. TKO ...
Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis.. Günther C, Martini E, Wittkopf N, Amann K, ... Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation. ... Cutting edge: innate immunity conferred by B cells is regulated by caspase-8. ...
Active caspase-8 initiates the subsequent cascade of caspases mediating apoptosis. Involved in interferon-mediated antiviral ... The resulting aggregate called the death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation. ... Apoptotic adaptor molecule that recruits caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors. ... R-HSA-5213460, RIPK1-mediated regulated necrosis. R-HSA-5218900, CASP8 activity is inhibited. R-HSA-5357786, TNFR1-induced ...
RIPK1 and caspase-8 ensure chromosome stability independently of their role in cell death and inflammation. Mol Cell. 2019;73(3 ... is the initiator caspase of the extrinsic apoptosis pathway that activates the effector caspase-3 (11). Cellular FLICE ... Caspase-8 serves both apoptotic and nonapoptotic roles. J Immunol. 2004;173(5):2976-2984.. View this article via: PubMed ... Caspase 8 inhibits programmed necrosis by processing CYLD. Nat Cell Biol. 2011;13(12):1437-1442.. View this article via: PubMed ...
RIPK1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved ER stress conditions Yann Estornes ( ... RIPK1-dependent cell death : a novel target of the Aurora kinase inhibitor Tozasertib (VX-680) Sofie Martens (UGent) , Vera ... RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis Nozomi Takahashi (UGent) , Lars Vereecke ( ...
RIPK1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved ER stress conditions Yann Estornes ( ... Degradomics reveals that cleavage specificity profiles of caspase-2 and effector caspases are alike Magdalena Wejda (UGent) , ... Proteome-wide substrate analysis indicates substrate exclusion as a mechanism to generate caspase-7 versus caspase-3 ... Caspase substrates: easily caught in deep waters? Dieter Demon (UGent) , Petra Van Damme (UGent) , Tom Vanden Berghe (UGent) , ...
Recombinant Mouse Ripk1 protein, His-tagged can be used for research. ... Purified Recombinant Mouse Ripk1 protein, His-tagged from Creative Biomart. ... Activation of Pro-Caspase 8, organism-specific biosystem; Apoptosis, organism-specific biosystem; Apoptosis, organism-specific ... Recombinant Mouse Ripk1 protein, His-tagged. Download Datasheet See All Ripk1 Products. Bring this labeled protein directly to ...
RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell. 2014;157(5):1189-1202. ... Hematopoietic RIPK1 deficiency results in bone marrow failure caused by apoptosis and RIPK3-mediated necroptosis. Proc Natl ... Figure 8. A working model for necroptosis-initiated autoimmune bone marrow failure (BMF). Antigens released from cells ... Our data suggest that necroptosis-Th1 response-Ifnγ is the axis of development of this disease (Figure 8). It might also ...
... the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis. Recent studies ... 8 (3): 197-204. doi:10.1007/s10456-005-9010-0. PMID 16328160. Mercurio, Arthur M; Bachelder, Robin E; Bates, Richard C; Chung, ... STAT3 and RANTES contribute to the maintenance of drug resistance by upregulating anti-apoptotic signals and inhibiting caspase ...
RIPK1 and Caspase-8 Ensure Chromosome Stability Independently of Their Role in Cell Death and Inflammation.. Mol Cell 73:413- ...
2014) RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3 Cell 157:1189-1202. ... 2019) Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis Nature 574:428-431. ... A) The body weights of 12-month-old Csnk1g2+/+, Csnk1g2−/−, and Csnk1g2−/− fed with a RIPK1 kinase inhibitor (RIPA-56)- ... 2002) c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis The EMBO Journal 21:3704-3714 ...
RIPK1+ cells) (33). Interestingly, we detected more active caspase-8 in microglia of MS lesions compared with those of normal ... UN, untreated; YVAD-fmk, caspase-1 inhibitor; IETD-fmk, caspase-8 inhibitor (n = 4/group). (G and H) FACS analysis of caspase-8 ... Dynamics of caspase-8 activation, IL-1β production, and IL-1R expression in microglia. (A and B) Analysis of results for WT→ASC ... Scale bars: 50 μm (C). The activated caspase-8+ cells were quantified (D). (E) EFYP+ primary microglia sorted from EAE mice ( ...
RIPK1 and RIPK3) to block the regulated necrosis pathway. When caspase 8 activation is blocked by microbial proteins like viral ... functions to activate caspase 8 to stimulate apoptosis. Caspase 8 also cleaves the RIP kinases ( ... 8). Since excellent reviews on pseudokinases are available that focus on their noncatalytic roles in signaling pathways (9-12 ... 8, 9). A classification scheme based on differences in nucleotide binding has recently been proposed ( ...
  • Cycloheximide promotes caspase-8 activation by eliminating endogenous caspase-8 inhibitor, c-FLIP, while Smac mimetic does so by triggering autodegradation of cIAP1 and cIAP2 (cIAP1/2), leading to the release of receptor interacting protein kinase (RIPK1) from the activated TNF receptor complex to form a caspase-8-activating complex consisting of RIPK1, FADD, and caspase-8. (nih.gov)
  • In accordance with increased cell death, HOIP-deficient hepatocytes displayed enhanced formation of a death-inducing signalling complex containing FADD, RIPK1, caspase-8 and c-FLIP. (bl.uk)
  • Collectively, these results identify LUBAC as a previously unrecognised tumour suppressor, which acts by restraining TNFR1-independent FADD-RIPK1-caspase-8 complex formation and caspase-8-dependent apoptosis, regardless of its gene-regulatory function, in hepatocytes to prevent liver damage and inflammation. (bl.uk)
  • I found that caspase-8 and receptor-interacting protein kinase-3 (RIPK3), RIPK1 and FADD are required for Yersinia-induced cell death. (upenn.edu)
  • FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. (springer.com)
  • Active caspase-8 initiates the degradative phase of apoptosis through activation of caspases-3/7 or blocks necroptosis via suppression of receptor-interacting serine/threonine protein kinase (RIPK)1-RIPK3 signaling, depending upon the availability of cellular FADD-like interleukin (IL)-1β-converting enzyme-inhibitory protein (cFLIP) [ 1 , 2 ]. (biomedcentral.com)
  • The necrosome contains numerous proteins, incuding RIPK1, FADD, caspase-8, and MLKL, and appears to serve a scaffolding function necessary for RIPK3 clustering and activation. (rupress.org)
  • Ablation of one allele of Fasl, Fadd, or Ripk1 prevented the pathology of Casp8D387A/D387AMlkl-/- animals. (bvsalud.org)
  • Removing both Fadd alleles from these mice resulted in early lethality prior to post-natal day 15 (P15), which was prevented by co-ablation of either Ripk1 or Caspase-1. (bvsalud.org)
  • Our results suggest an in vivo role of the inflammatory RIPK1-caspase-8-FADD (FADDosome) complex and reveal a FADD-independent inflammatory role of caspase-8 that involves activation of an inflammasome. (bvsalud.org)
  • FADD is a common adaptor shared by several death receptors for signalling apoptosis through recruitment and activation of caspase 8 (refs 1-3). (jefferson.edu)
  • FADD could directly bind to RIP1 (also known as RIPK1), a serine/threonine kinase that mediates both necrosis and NF-κB activation. (jefferson.edu)
  • Caspase-8 and its regulator cFLIP control death signaling by binding to death-receptor-bound FADD. (icr.ac.uk)
  • on Canagliflozin price RIPK3-mediated necroptosis through the FADD, Caspase-8 pathway. (hiv-proteases.com)
  • Upon IAV infection, RIPK3 nucleates a necrosome complex, that minimally also includes receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and mixed lineage kinase domain-like (MLKL), which then activates both apoptosis, via a RIPK1+Fas-Associated protein with Death Domain (FADD)+Caspase 8 axis, and necroptosis, mediated by MLKL. (justia.com)
  • The caspase-8 adaptor FADD was recruited to ASC specks, which served as cytosolic platforms for caspase-8 activation and NLRP1b/NLRC4-induced apoptosis. (readbyqxmd.com)
  • Inhibition of RIPK3-MLKL-dependent necroptosis by FADD and caspase-8 was identified as a key mechanism preventing inflammation in epithelial barriers. (uni-koeln.de)
  • The adapter molecule FADD recruits caspase-8 to the activated receptor. (genecards.org)
  • MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. (edu.au)
  • Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. (ethz.ch)
  • d Annexin-V/PI flow cytometry (Left) and cell viability assay (Right) in PC3 cells pre-treated for 1 h with 20 µM Necrostatin-1 (RIPK1 kinase inhibitor), GSK'840 (RIPK3 kinase inhibitor Necrosulfonamide (MLKL inhibitor) followed by pre-treatment for 24 h with 2.5 µM Entinostat(Ent) and a further 24 h with 1 µM TL32711 and 10 ng/mL TNFα combination. (nature.com)
  • The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis 8 . (nature.com)
  • Loss of RIPK1 kinase activity also prevented Ripk1 D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. (nature.com)
  • Consistently, Ripk1 D325A/D325A and Ripk1 D325A /+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. (nature.com)
  • Catalytic activity of the caspase-8-FLIP L complex inhibits RIPK3-dependent necrosis. (nature.com)
  • RIPK1 recruits RIPK3 and they phosphorylate each other. (news-medical.net)
  • Kinase activity of RIPK1 is also required for RIPK1-dependent apoptosis in conditions of IAP1/2 depletion, TAK1inhibition/depletion, RIPK3 depletion or MLKL depletion. (wikipedia.org)
  • Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 trigger pro-inflammatory cell death termed necroptosis. (sciencemag.org)
  • Studies with RIPK3-deficient mice or the RIPK1 inhibitor necrostatin-1 suggest that necroptosis exacerbates pathology in many disease models. (sciencemag.org)
  • We engineered mice expressing catalytically inactive RIPK3 D161N or RIPK1 D138N to determine the need for the active kinase in the whole animal. (sciencemag.org)
  • Unexpectedly, RIPK3 D161N promoted lethal RIPK1- and caspase-8-dependent apoptosis. (sciencemag.org)
  • In contrast, mice expressing RIPK1 D138N were viable and, like RIPK3-deficient mice, resistant to tumor necrosis factor (TNF)-induced hypothermia. (sciencemag.org)
  • Our data indicate that the kinase activity of RIPK3 is essential for necroptosis, but also governs whether a cell activates caspase-8 and dies by apoptosis. (sciencemag.org)
  • CSNK1G2-knockout mice showed significantly enhanced necroptosis response and premature aging of their testis, a phenotype that was rescued by either double knockout of the Ripk3 gene or feeding the animal with a RIPK1 kinase inhibitor-containing diet. (elifesciences.org)
  • Necroptosis is actively suppressed by caspase-8-mediated cleavage of RIPK1 and RIPK3, whose upstream activation pathway is often shared between caspase-8 and RIPK1 kinase. (elifesciences.org)
  • Two protein kinases, known as RIPK1 and RIPK3 promote signaling that leads to cell death by necroptosis. (sciencemag.org)
  • Instead, mice expressing a form of RIPK3 with no catalytic activity died from increased apoptotic cell death, but animals lacking the RIPK3 protein entirely, did not die perhaps because RIPK3 restrains apoptosis mediated by caspase-8 by an independent mechanism. (sciencemag.org)
  • TRIF may also recruit the necrosome components RIPK1, RIPK3, and MLKL, leading to necroptosis. (sciencemag.org)
  • Inhibition of RIPK1 kinase activity alone, or caspase inhibition combined with RIPK3 deletion, abrogates IEC death by blocking both apoptosis and necroptosis in A20 and ABIN-1 double-deficient cells. (rupress.org)
  • Necroptosis is a form of regulated necrotic cell death, which is mediated by receptor-interacting protein 1 kinase (RIPK1) and RIPK3, and the downstream effector mixed lineage kinase domain-like (MLKL). (springer.com)
  • RIPK1 and RIPK3 kinases promote cell death independent inflammation by TLR4-TRIF. (tufts.edu)
  • In this work, I describe a previously unappreciated role the kinase activities of RIPK1 and RIPK3 in primary macrophages in directing inflammatory gene expression downstream from TLR4 that manifest independently of cell death. (tufts.edu)
  • Using this in vitro system, I further established that kinase activities of RIPK1 and RIPK3 induce acute inflammatory cytokine mRNA expression and protein release. (tufts.edu)
  • The transcription factors, cFos and NF-B are also required for RIPK1 and RIPK3 dependent inflammatory responses. (tufts.edu)
  • Importantly, using genetic and pharmacologic tools, I found that RIPK1 and RIPK3 account for the major fraction of the acute inflammatory responses elicited by LPS in vivo even in the absence of exogenous inhibition of caspase-8. (tufts.edu)
  • Overall, these findings provide new insights into RIPK1 and RIPK3 kinase functions in the context of innate immune responses and identify new drug-targetable activities that may be highly relevant to the mechanisms of RIPK1/3-dependent inflammatory pathologies. (tufts.edu)
  • Caspase (CASP)8 is an autoactivating aspartate-specific cysteine protease that initiates extrinsic apoptosis and prevents receptor interacting protein (RIP) kinase (RIPK)1-RIPK3-driven necroptosis. (escholarship.org)
  • Ripk1-/-Casp8-/-Ripk3-/- mice fail to show the enhanced expansion of lymphocytes observed in Casp8-/-Ripk3-/- mice even though development and homeostasis are preserved in uninfected Ripk1-/-Casp8-/-Ripk3-/- mice. (escholarship.org)
  • In addition, the expression levels of RIPK1, RIPK3, and MLKL were analyzed by western blotting, and the activities of caspase-3 and caspase-8 and levels of reactive oxygen species (ROS) were assessed. (dovepress.com)
  • Moreover, RIPK1, RIPK3, and MLKL were upregulated by shikonin in a dose-dependent manner. (dovepress.com)
  • Shikonin induced 5-8F cell death via increased ROS production and the upregulation of RIPK1/RIPK3/MLKL expression, resulting in necroptosis. (dovepress.com)
  • TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation. (springer.com)
  • Loss of caspase-8 expression in macrophages promotes onset of a mild systemic inflammatory disease, which is preventable by the deletion of RIPK3. (biomedcentral.com)
  • As a scaffold, RIPK1 inhibits caspase-8-dependent apoptosis and RIPK3/MLKL-dependent necroptosis. (umayor.cl)
  • Activation of these inflammatory pathways required RIPK3 kinase activity while RIPK1 was dispensable. (hiv-proteases.com)
  • However, loss of RIPK1 sensitizes macrophages to activate RIPK3 in response to inflammatory stimuli, thereby exacerbating Canagliflozin price a potentially pathological inflammatory response. (hiv-proteases.com)
  • There are two basic conditions for necroptosis: (1) cells must express RIPK3 and (2) inhibition of caspase-8 molecule. (biomedcentral.com)
  • In the skin, RIPK1 functions via its RHIM to counteract ZBP1/DAI-dependent activation of RIPK3-MLKL-dependent necroptosis and inflammation. (uni-koeln.de)
  • Genetic deletion and mitosis-specific inhibition of Ripk1 or Caspase-8 results in chromosome alignment defects independently of MLKL. (edu.au)
  • Necroptosis was determined via viability assays and immunohistochemistry for receptor-interacting protein kinase-1 (RIPK1), mixed lineage kinase domain-like protein (MLKL) and caspase-3. (physiciansweekly.com)
  • Inhibition of RIPK1 or MLKL attenuated RSV-induced HMGB1 translocation and release, and lowered viral load. (physiciansweekly.com)
  • MLKL inhibition increased active caspase-3 expression in a caspase-8/9-dependent manner. (physiciansweekly.com)
  • Genetic or pharmacological inhibition of RIPK1 or MLKL attenuated these pathologies, lowered viral load, and prevented type-2 inflammation and airway remodelling. (physiciansweekly.com)
  • Moreover, combined ablation of systemic caspase-8 and MLKL completely prevented liver damage due to loss of HOIP, whereas MLKL deficiency did not have a beneficial effect. (bl.uk)
  • Although neither mouse developed LPR disease, removal of the necroptosis effector Mlkl from Caspase-8D387A/D387A mice revealed an inflammatory role of caspase-8. (bvsalud.org)
  • Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3. (umassmed.edu)
  • Thus, CASP8 naturally regulates the magnitude of NK cell responses in response to infection where strong activation signals depend on another key regulator of death signaling, RIPK1. (escholarship.org)
  • TLR4 (zeige TLR4 Proteine ) activates CASPASE-8 (zeige CASP8 Proteine ) to cleave and remove the deubiquitinase cylindromatosis ( CYLD ) in a TRIF (zeige RNF138 Proteine )- and RIPK1 (zeige RIPK1 Proteine )-dependent manner to disable necroptosis in macrophages. (antikoerper-online.de)
  • On www.antibodies-online.com are 406 Caspase 8, Apoptosis-Related Cysteine Peptidase (CASP8) Antibodies from 37 different suppliers available. (antibodies-online.com)
  • Loss of caspase-8 in macrophages dictates the response to TLR activation, as injection of TLR ligands upregulates expression of costimulatory CD86 on the Ly6C high CD11b + F4/80 + splenic cells, and oral antibiotic treatment to remove microbiota prevents splenomegaly and lymphadenopathy in Cre LysM Casp8 fl/fl mice. (biomedcentral.com)
  • Caspase-8 is a caspase protein, encoded by the CASP8 gene. (wikipedia.org)
  • The CASP8 gene encodes a member of the cysteine - aspartic acid protease ( caspase ) family. (wikipedia.org)
  • Here, using Yersinia pseudotuberculosis in corroboration with costimulation of lipopolysaccharide and (5Z)-7-Oxozeaenol, a small-molecule inhibitor of TAK1, we show that caspase-8 activation during TAK1 inhibition results in cleavage of both gasdermin D (GSDMD) and gasdermin E (GSDME) in murine macrophages, resulting in pyroptosis. (pnas.org)
  • The KD can also interact with Necrostatin-1, which is an allosteric inhibitor of RIPK1 kinase activity. (wikipedia.org)
  • Biochemically, caspase-8 was found to enter the complex of the inhibitor of NF-κB kinase (IKK) with the upstream Bcl10-MALT1 (mucosa-associated lymphatic tissue) adapter complex which were crucial for the induction of nuclear translocation of NF-κB. (wikipedia.org)
  • Acts as an inhibitor of the caspase cascade (PubMed:12010809). (icr.ac.uk)
  • High molecular weight proteins reacting with the RIPK1 antibody increased in the presence of CM and were reduced upon incubation with the BIRC3 inhibitor AT406 in C7 cells suggesting that they represent ubiquitinated forms of RIPK1. (manchester.ac.uk)
  • Birinapant, also known as TL32711, is a synthetic small molecule and peptido mimetic of second mitochondrial-derived activator of caspases (SMAC) and inhibitor of IAP (Inhibitor of Apoptosis Protein) family proteins, with potential antineoplastic activity. (newdrugapprovals.org)
  • Inhibitors of apoptosis proteins (IAP) are key regulators of apoptosis and are inhibited by the second mitocondrial activator of caspases (SMAC). (aacrjournals.org)
  • Cancer cells avoid apoptosis by upregulation of antiapoptotic factors such as the inhibitors of apoptosis proteins (IAP), which bind caspases and sequester them or inhibit their protease activity ( 2 ). (aacrjournals.org)
  • The human IAP family contains 8 proteins, most notably cIAP1, cIAP2, and X-chromosome-encoded IAP (XIAP). (aacrjournals.org)
  • The adaptor TRIF engages the kinase RIPK1 and the ubiquitin (Ub) ligase Pellino1, and ubiquitylation of RIPK1 by Pellino1 then enables recruitment of the kinase TAK1 and the TAK1-binding proteins TAB2/3 and the IκB kinase (IKK) complex. (sciencemag.org)
  • Within this family of proteins is caspase-8, which is unusual as it can promote both cell death, and inflammatory gene expression induced by Toll-like Receptors. (upenn.edu)
  • The direct cleavage of caspases ( 2 ), disruption of nuclear-cytoplasmic trafficking ( 3 , 4 ), relocalization of proapoptotic proteins ( 5 , 6 ), and cleavage of essential apoptotic adaptor proteins ( 7 , 8 ) have all been shown to occur as a result of action of Picornavirus protease activity and together suggest mechanisms by which picornaviruses can alter host cell apoptotic death pathways. (asm.org)
  • Additionally we are shipping Caspase 8 Kits (72) and Caspase 8 Proteins (26) and many more products for this protein. (antibodies-online.com)
  • These proteins interact with IPS-1 and activate NF-kB through interaction and activation of caspase-8 and caspase-10. (reactome.org)
  • The best well-known pathway of NF-kB activation is that mediated by the death receptor TNFR1, which starts as in the necroptosis pathway with the assembly of TRADD, RIPK1, TRAF2 and clAP1 in the lipid rafts of the plasma membrane (complex I is formed). (wikipedia.org)
  • Upon DNA damage, RIPK1 mediates another NF-kB activation pathway where two simultaneous and exclusive processes occur. (wikipedia.org)
  • Furthermore, genetic and pharmacological suppression of RIPK1 has been shown to revert the phenotype of AD and its mediating pathway is yet to be deciphered. (eurekaselect.com)
  • These pathways differ by the upstream signals that activate them and the initiator caspase involved: caspase 9 in the mitochondrial pathway, caspase 8 or 10 in the death receptor pathway, and caspase 4 in the ER stress pathway ( 11 ). (aacrjournals.org)
  • Feng S, Yang Y, Mei Y, Ma L, Zhu DE, Hoti N, Castanares M, Wu M (2007) Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. (springer.com)
  • However, inhibition of TNFα-induced apoptosis in TEC through caspase-8 upregulated the receptor interacting protein kinase 1 and 3 (RIPK1/3)-mediated necroptosis pathway to limit graft survival. (uwo.ca)
  • For the death pathway, the caspase-8 zymogen is cleaved into subunits that assemble to form the mature, highly active caspase heterotetramer whereas for the activation pathway, the zymogen appears to remain intact perhaps to limit its proteolytic function but enhance its capability as an adapter protein. (wikipedia.org)
  • Because some viruses require Capital t cell expansion for replication, this, in change, serves as a sensor to prevent Capital t cell growth in the absence of a practical AV-412 caspase-dependent apoptotic pathway. (bx-912.com)
  • Because Trif, but not additional adapters, interacts with Ripk1, we propose that Tlr3,4 service engages Ripk1, and without caspase-8, M cells pass away via the necroptosis pathway. (bx-912.com)
  • Hence, it is an alternative mode of cell death when caspase-8-dependent apoptotic pathway is blocked. (biomedcentral.com)
  • Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production. (edu.au)
  • To define the mechanism for this disease, we generated a cleavage-resistant Ripk1 D325A mutant mouse strain. (nature.com)
  • Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life. (nature.com)
  • Fig. 1: Heterozygous mutations of the RIPK1 caspase-8 cleavage site cause autoinflammatory disease. (nature.com)
  • Fig. 2: Homozygous mutation of the RIPK1 caspase-8 cleavage site in mice causes early embryonic lethality. (nature.com)
  • Fig. 4: RIPK1 cleavage limits inflammation in vivo. (nature.com)
  • We found that Polo-like kinase 1 (PLK1) is recruited into mitotic ripoptosomes, where PLK1's activity is controlled via RIPK1-dependent recruitment and Caspase-8-mediated cleavage. (edu.au)
  • Here we demonstrate that Yersinia YopJ-induced murine macrophage death involves caspase-8-induced cleavage of both gasdermin D (GSDMD) and gasdermin E (GSDME). (pnas.org)
  • Our work extends these studies and shows that activation of caspase-8 in the context of TAK1 inhibition results in cleavage of both GSDMD and GSDME, leading to pyroptotic-like cell death. (pnas.org)
  • Also, proteolytic processing of RIPk1, through both caspase-dependent and -independent mechanisms, triggers lethality that is dependent on the generation of one or more specific C-terminal cleavage product(s) of RIPk1 upon stress. (wikipedia.org)
  • Our data indicate that CK acts as substrate adaptor, recruiting SHAGGY46/GSK3-β to DRONC, thereby facilitating caspase-mediated cleavage and localized modulation of kinase activity. (qmul.ac.uk)
  • This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. (ethz.ch)
  • We found that Ripk1-deficient MEFs are protected from apoptosis induced by ER stressors, which is reflected by reduced caspase activation and PARP processing. (nuigalway.ie)
  • Instead, we found that ER stress-induced apoptosis in these cells relies on death receptor-independent activation of caspase-8, and identified Ripk1 upstream of caspase-8. (nuigalway.ie)
  • Our data rather suggest that RIPK1 indirectly regulates caspase-8 activation, in part via interaction with the ER stress sensor inositol-requiring protein 1 (IRE1). (nuigalway.ie)
  • RIPK1 is critical for caspase-8 activation-induced by Smac mimetic but dispensable for that triggered by cycloheximide. (nih.gov)
  • Moreover, Smac mimetic-induced caspase-8 activation is not blocked by endogenous c-FLIP. (nih.gov)
  • These findings revealed that TNF-alpha is able to induce apoptosis via two distinct caspase-8 activation pathways that are differentially regulated by cIAP1/2 and c-FLIP. (nih.gov)
  • Complex IIa is involved in caspase 8 activation, which leads to apoptosis. (news-medical.net)
  • Recently, both GSDMD and GSDME were reported to be critical effectors of caspase-1/11-driven pyroptosis and caspase-3-dependent secondary necrosis, which prompted the redefinition of pyroptosis as cell death-mediated by gasdermin activation. (pnas.org)
  • While being in complex I, RIPK1 has also been proved to play a role in the activation of MAP (mitogen-activated protein) kinases such as JNK, ERK and p38. (wikipedia.org)
  • A pro-apoptotic complex is created while RIPK1 also mediates the interaction between PIDD, NEMO and IKK subunits that will eventually result in the IKK complex activation after interaction with ATM kinase (a DNA double-strand breaks stimulated protein). (wikipedia.org)
  • Establishing the role of RIPK1-death domain (DD) in mediating RIPK1 activation and formation of complex II provides an important insight into the molecular mechanism by which RIPK1 is activated during the transition from complex I to complex II. (pnas.org)
  • These results suggest that RIPK1-DD self-association may provide an amplification mechanism to promote the activation of RIPK1 kinase activity for mediating signal transduction to lead to cell death. (pnas.org)
  • Our results also suggest that the activation of RIPK1 may be regulated by its concentration as increased expression of RIPK1 under pathological conditions may promote its dimerization and activation. (pnas.org)
  • RIPK1 Mediates TNF-Induced Intestinal Crypt Apoptosis During Chronic NF-κB Activation. (nih.gov)
  • The resulting aggregate called the death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation. (uniprot.org)
  • These effects were accompanied by caspase 3, 4, and 9 activation, indicating that both mitochondrial and endoplasmic reticulum stress-induced apoptotic pathways are activated by the combination of vinorelbine and JP1201. (aacrjournals.org)
  • The recruitment of cIAP1 and cIAP2 to TNFR1 inhibits TNF-α-dependent, RIPK1-dependent activation of caspase 8 ( 4-9 ). (aacrjournals.org)
  • Activation of TNFR1 by TNF-α induces the assembly of complex I, which includes TRADD, TRAF2 or TRAF5, RIPK1, and cIAPs. (sciencemag.org)
  • Studies with enteroids reveal that A20 and ABIN-1 synergistically restrict death by inhibiting TNF-induced caspase 8 activation and RIPK1 kinase activity. (rupress.org)
  • Conditional deletion of caspase-8 in macrophages alters macrophage activation in a RIPK-dependent manner. (bio-protocol.org)
  • Caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation. (bio-protocol.org)
  • In TNF-stimulated cells, RIPK1 promotes cell survival by stabilizing TRAF2 and cIAP1, which limits induction of non-canonical NF-k B and activation of caspase-8. (uniklinik-freiburg.de)
  • Wong WW, Gentle IE, Nachbur U, Anderton H, Vaux DL, Silke J. RIPK1 is not essential for TNFR1-induced activation of NF-kB. (uniklinik-freiburg.de)
  • Most upstream protease of the activation cascade of caspases responsible for the TNF RSF6/ FAS mediated and TNF RSF1A induced cell death (PubMed:24813849, PubMed:24813850). (sdsc.edu)
  • My studies also showed that caspase-8 is required for the activation of caspase-1 and -3 during Yersinia infection. (upenn.edu)
  • Boesen-de Cock, Tepper, de Vries, van Blitterswijk, Borst: Common regulation of apoptosis signaling induced by CD95 and the DNA-damaging stimuli etoposide and gamma-radiation downstream from caspase-8 activation. (antibodies-online.com)
  • Further, caspase-8-deficient macrophages are hyperresponsive to TLR activation and exhibit aberrant M1 macrophage polarization due to RIPK activity. (biomedcentral.com)
  • These data demonstrate that caspase-8 functions uniquely in macrophages by controlling the response to TLR activation and macrophage polarization in an RIPK-dependent manner. (biomedcentral.com)
  • We previously showed that conditional deletion of Fas or caspase-8 specifically in innate immune cells supports a role for these signaling components in cell activation. (biomedcentral.com)
  • Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis . (wikipedia.org)
  • Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. (wikipedia.org)
  • The defect in lymphocyte activation and protective immunity suggested that caspase-8 had additional signaling roles in lymphocytes . (wikipedia.org)
  • Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival. (icr.ac.uk)
  • Apoptosis is an evolutionary conserved cell death mechanism, which requires activation of initiator and effector caspases. (icr.ac.uk)
  • Essential adapter molecule for the activation of NF-kappa-B. Following different upstream signals (binding of inflammatory cytokines, stimulation of pathogen recognition receptors, or DNA damage), particular RIPK1-containing complexes are formed, initiating a limited number of cellular responses. (abcam.com)
  • Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death (PubMed:23516580, PubMed:8681376, PubMed:8681377, PubMed:9006941, PubMed:9184224). (icr.ac.uk)
  • In line with their roles in IKK activation, TNF-induced Ser25 phosphorylation of RIPK1 is defective in TAK1- or SHARPIN-deficient cells and restoring phosphorylation protects these cells from TNF-induced death. (umayor.cl)
  • The caspase activation and recruitment domain (CARD)-based inflammasome sensors NLRP1b and NLRC4 induce caspase-1-dependent pyroptosis independent of the inflammasome adaptor ASC. (readbyqxmd.com)
  • Activation of ICE-family proteases/caspases initiates apoptosis in mammalian cells. (genetex.com)
  • The binding of this protein to its receptors has been shown to trigger the activation of MAPK8/JNK, caspase 8, and caspase 3. (genecards.org)
  • The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis (PubMed:19090789). (genecards.org)
  • Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. (edu.au)
  • Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. (edu.au)
  • In this study, we identified receptor interacting protein kinase 1 (RIPK1)-a kinase at the crossroad between life and death downstream of various receptors-as a new regulator of ER stress-induced death. (nuigalway.ie)
  • Receptor-interacting protein kinase (RIPK) 1 functions as a key mediator of tissue homeostasis via formation of Caspase-8 activating ripoptosome complexes, positively and negatively regulating apoptosis, necroptosis, and inflammation. (edu.au)
  • Recently, receptor-interacting protein kinase 1 (RIPK1) has been identified as a key component in the pathogenesis of AD through necroptosis. (eurekaselect.com)
  • Duprez L, Bertrand MJ, Vanden Berghe T, Dondelinger Y, Festjens N, Vandenabeele P (2012) Intermediate domain of receptor-interacting protein kinase 1 (RIPK1) determines switch between necroptosis and RIPK1 kinase-dependent apoptosis. (springer.com)
  • Receptor-interacting protein kinase 1 (RIPK1) induces apoptosis and necroptosis via kinase-dependent mechanisms and exhibits kinase-independent prosurvival and proinflammatory functions. (jci.org)
  • Interestingly, necroptosis is inhibited by Necrostatin-1 (Nec-1) by inhibiting the activity of receptor-interacting protein kinase 1 (RIPK1), which suggests that it is a well-regulated process or programmed necrosis. (biomedcentral.com)
  • The enzyme caspase-8 induces a molecular cell death programme called pyroptosis without involving its enzymatic activity, a new study by Hamid Kashkar published in Nature shows. (news-medical.net)
  • As a kinase, RIPK1 paradoxically induces these cell death modalities. (umayor.cl)
  • Panobinostat induces HIV-1 virus production even at low concentration range 8-31 nM, stimulates HIV-1 expression in latently infected cells. (medchemexpress.com)
  • However, inhibition of RIPK1/3 necroptotic death during renal IRI and transplantation was able to preserve renal function and promote long term graft survival. (uwo.ca)
  • RIPK1 is a key regulator of innate immune signalling pathways. (nature.com)
  • Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions in a variety of cellular pathways related to both cell survival and death. (wikipedia.org)
  • Some of the cell survival pathways RIPK1 participates in include NF-κB, Akt, and JNK. (wikipedia.org)
  • It has been shown that cell survival can be regulated through different RIPK1-mediated pathways that ultimately result in the expression of NF-kB, a protein complex known to regulate transcription of DNA and thus, related to survival processes. (wikipedia.org)
  • Cells expressing RIPK1 D138N were resistant to TNF-induced necroptosis, whereas TNF-induced signaling pathways promoting gene transcription were unperturbed. (sciencemag.org)
  • The extrinsic and intrinsic apoptosis pathways converge to cleave and activate procaspase-3 to derive caspase 3, which is termed an executioner caspase. (asm.org)
  • Caspase-8 is intimately involved in two essential death pathways-apoptosis and necroptosis-that are responsible for the fate of a cell. (biomedcentral.com)
  • Moreover, the biochemical form of caspase-8 differed in the two pathways. (wikipedia.org)
  • An inhibitory mono-ubiquitylation of the Drosophila initiator caspase Dronc functions in both apoptotic and non-apoptotic pathways. (icr.ac.uk)
  • Capital t cells enigmatically require caspase-8, an inducer of apoptosis, for antigen-driven growth and effective antiviral reactions, and yet the pathways responsible for this effect possess been evasive. (bx-912.com)
  • MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death. (nature.com)
  • Multiple caspases are activated during Yersinia infection, including caspase-1, which regulates pyroptosis, and caspase-3 and -8, which elicit apoptosis. (upenn.edu)
  • Since uncleaved caspase-8 functions together with its homolog, cFLIP, our findings implicate the activity of a caspase-8/cFLIP heterodimer in control of inflammatory cytokines during microbial infection, and provide new mechanistic insight into how caspase-8 regulates gene expression. (upenn.edu)
  • Here we find that the Drosophila unconventional myosin CRINKLED (CK) selectively interacts with the initiator caspase DRONC and regulates some of its non-apoptotic functions. (qmul.ac.uk)
  • RIPK1 regulates cell death and inflammation through kinase-dependent and -independent mechanisms. (umayor.cl)
  • NF-κB-independent role of IKKα/IKKβ in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. (nature.com)
  • Whereas Ripk1 −/− mice died postnatally from systemic inflammation, Ripk1 D325A/D325A mice died during embryogenesis. (nature.com)
  • p38 MAPK /MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection. (nature.com)
  • Here, we report an unanticipated cell-death- and inflammation-independent function of RIPK1 and Caspase-8, promoting faithful chromosome alignment in mitosis and thereby ensuring genome stability. (edu.au)
  • Because caspase-8 mediates CD95 signaling, we applied genetic approaches to dissect the roles of caspase-8 in cell death and inflammation. (bvsalud.org)
  • Caspases provide vital links in non-apoptotic regulatory networks controlling inflammation, compensatory proliferation, morphology and cell migration. (qmul.ac.uk)
  • Moreover, the interplay between IKK/NF-κB and RIPK1 signaling was recognized as a critical determinant of tissue homeostasis and inflammation. (uni-koeln.de)
  • NEMO was shown to regulate RIPK1 kinase activity-mediated apoptosis by NF-κB-dependent and -independent functions, which are critical for averting chronic tissue injury and inflammation in the intestine and the liver. (uni-koeln.de)
  • In addition, RIPK1 was shown to exhibit kinase activity-independent functions that are essential for preventing cell death, maintaining tissue architecture and inhibiting inflammation. (uni-koeln.de)
  • This process also requires the action of CYLD, a RIPK1 K63 deubiquitinating enzyme. (nih.gov)
  • Heterozygous Ripk1 D325A /+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. (nature.com)
  • Further deletion of the BH3-only member Bid (to generate Vav CreBaxBakBid triple-knockout [TKO] mice) leads to unrestrained bone marrow necroptosis driven by increased Rip1 kinase (Ripk1). (bloodjournal.org)
  • Necroptosis was blocked using pharmacological inhibitors, and RIPK1 kinase-dead knock-in mice. (physiciansweekly.com)
  • Interestingly, mice lacking caspase-8 were severely susceptible to Yersinia infection and had defective pro-inflammatory cytokine production. (upenn.edu)
  • Using mice that specifically ablate caspase-8 auto-processing, I have demonstrated that caspase-8 enzymatic, but not autoprocessing activity, mediates induction of inflammatory cytokines by a wide variety of TLR stimuli. (upenn.edu)
  • Our data demonstrate that inefficient negative selection in the thymus of CYLD (ex7/8) mice result from a defect in mTEC maturation. (antikoerper-online.de)
  • yet, caspase-8-deficient macrophages are not predisposed to unchecked survival, as analysis of mixed bone marrow chimeric mice demonstrates that caspase-8 deficiency does not confer preferential expansion of myeloid populations. (biomedcentral.com)
  • Here, we describe oligomerization-deficient Caspase-8F122GL123G/F122GL123G and non-cleavable Caspase-8D387A/D387A mutant mice with defective caspase-8-mediated apoptosis. (bvsalud.org)
  • While ablating either RIPK1 or RelA in liver parenchymal cells (LPCs) did not cause spontaneous liver pathology, mice with combined deficiency of RIPK1 and RelA in LPCs showed increased hepatocyte apoptosis and developed spontaneous chronic liver disease and cancer that were independent of TNF receptor 1 (TNFR1) signaling. (jci.org)
  • In contrast, mice with LPC-specific knockout of Ripk1 showed reduced diethylnitrosamine-induced (DEN-induced) liver tumorigenesis that correlated with increased DEN-induced hepatocyte apoptosis. (jci.org)
  • I found that upon the loss of caspase-8 in vitro, RIPK1 kinase activity is markedly elevated in primary macrophages in response to TLR4 agonist lipopolysaccharide (LPS). (tufts.edu)
  • As cells of the innate immune system, and in particular macrophages, are now at the forefront of autoimmune disease pathogenesis, we examined the potential involvement of caspase-8 within this population. (biomedcentral.com)
  • Here, we show that NLRP1b and NLRC4 trigger caspase-8-mediated apoptosis as an alternative cell death program in caspase-1-/- macrophages and intestinal epithelial organoids (IECs). (readbyqxmd.com)
  • Active caspase-8 initiates the subsequent cascade of caspases mediating apoptosis. (uniprot.org)
  • Pathogenic Yersinia inhibits the MAP kinase TGFβ-activated kinase 1 (TAK1) via the effector YopJ, thereby silencing cytokine expression while activating caspase-8-mediated cell death. (pnas.org)
  • inhibits caspase 7 with an IC 50 of 48 nM and 25-400 nM for other caspases including caspase 1, 3, 8, 9, 10, and 12. (medchemexpress.com)
  • TBK1 and IKKε prevent TNF-induced cell death by RIPK1 phosphorylation. (nature.com)
  • We identify phosphorylation of RIPK1 on Ser25 by IKKs as a key mechanism directly inhibiting RIPK1 kinase activity and preventing TNF-mediated RIPK1-dependent cell death. (umayor.cl)
  • Caspases exist as inactive proenzymes composed of a prodomain , a large protease subunit , and a small protease subunit. (wikipedia.org)
  • The clinical phenotype of CEDS patients represented a paradox since caspase-8 was considered to be chiefly a proapoptotic protease , that was mainly involved in signal transduction from Tumor necrosis factor receptor family death receptors such as Fas. (wikipedia.org)
  • Although caspase-8 is a well-established initiator of apoptosis and suppressor of necroptosis, recent evidence suggests that this enzyme maintains functions beyond its role in cell death. (biomedcentral.com)
  • In response to autocrine TNFalpha signaling, the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis. (nih.gov)
  • Our previous work aimed to develop second mitochondrial activator of caspases (SMAC) mimetics to target cancer cell-specific alterations ( 6 , 9 , 12, 13 ). (aacrjournals.org)
  • However, in contrast to RIPK1-dependent apoptosis downstream of TNFR1, we did not find Ripk1 associated with caspase-8 in a death-inducing complex upon unresolved ER stress. (nuigalway.ie)
  • Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death. (nih.gov)
  • Apoptotic adaptor molecule that recruits caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors. (uniprot.org)
  • cIAP-mediated K63-linked ubiquitylation of RIPK1 recruits the TAB2/3-TAK1 complex and the IKK complex. (sciencemag.org)
  • Interacts with RIPK1 (PubMed:31519887). (sdsc.edu)
  • Interacts with RIPK1 (By similarity). (icr.ac.uk)
  • Caspases are proteases that are best characterized for their abilities to regulate apoptotic or pyroptotic cell death programs, both of which are critical for the proper operation of the mammalian immune system. (upenn.edu)
  • The unconventional myosin CRINKLED and its mammalian orthologue MYO7A regulate caspases in their signalling roles. (qmul.ac.uk)
  • Cytosolic caspase-8 is a mediator of death receptor signaling. (bvsalud.org)
  • We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. (edu.au)
  • This subsequently leads to the recruitment of a complex, called the prosurvival complex I. This is composed of TNF-receptor-associated death domain (TRADD), polyubiquitinated RIPK1 and ubiquin E3 ligases. (news-medical.net)
  • IKK complex recruitment is further facilitated through LUBAC-mediated, M1-linked ubiquitylation of RIPK1. (sciencemag.org)
  • This protein aggregation facilitates recruitment of the cysteine-aspartic acid enzyme pro-caspase-8, which becomes active upon dimerization. (biomedcentral.com)
  • This protein belongs to the Receptor Interacting Protein (RIP) kinases family, which consists of 7 members, RIPK1 being the first member of the family. (wikipedia.org)
  • Together, our results expose a conserved role for unconventional myosins in transducing caspase-dependent regulation of kinases, allowing them to take part in specific signalling events. (qmul.ac.uk)
  • There is slow but constant turnover of respiratory epithelial cells via programmed cell death at homeostasis, with cells completely renewed every 30-50 days ( 8 ). (frontiersin.org)
  • Here, we have used genetic mouse models to study the role of RIPK1 in liver homeostasis, injury, and cancer. (jci.org)
  • Finally, we show that Bid impacts necroptotic signaling through modulation of caspase-8-mediated Ripk1 degradation. (bloodjournal.org)
  • In survival signalling, RIPK1 is then polyubiquitinated, allowing NEMO (Necrosis Factor - kappa - B essential modulator) to bind to the IkB kinase or IKK complex. (wikipedia.org)
  • Scientists at St. Jude Children's Research Hospital have discovered a new way that the molecule RIPK1 leads to cell death in infected, damaged or unwanted cells showing that more than one mechanism can trigger the process. (news-medical.net)
  • Further study will be needed to determine whether caspase-8 cleaves GSDMD directly or via intermediate substrates. (pnas.org)
  • Cleaves RIPK1 at 'Asp-325', which is crucial to inhibit RIPK1 kinase activity, limiting TNF -induced apoptosis, necroptosis and inflammatory response (PubMed:31511692). (sdsc.edu)
  • MK2 phosphorylates RIPK1 to prevent TNF-induced cell death. (nature.com)
  • For example, the vaccinia virus possesses inhibitors of both caspase 1 and 8, which are required for apoptosis, and therefore without necroptosis this infection could avoid cell death. (news-medical.net)
  • In terms of cell death, RIPK1 plays a role in apoptosis and necroptosis. (wikipedia.org)
  • The interaction between RIPK1 and PIDD through their death domains is thought to promote cell survival to neutralize this pro-apoptotic complex. (wikipedia.org)
  • Genetically restoring Ripk1 to wild-type levels restores peripheral red cell counts as well as normal cytokine production. (bloodjournal.org)
  • RSV-induced epithelial cell death was associated with increased pRIPK1 and pMLKL, but not active caspase-3 expression. (physiciansweekly.com)
  • Caspase-8 restricts natural killer cell accumulation during MCMV Infection. (escholarship.org)
  • Lavrik, Golks, Krammer: Caspases: pharmacological manipulation of cell death. (antibodies-online.com)
  • Whereas apoptosis results in orderly, caspase-driven disassembly of the cell into discrete membrane-bound vesicles, necroptosis culminates in a cellular "explosion" that spills the cell's contents into the extracellular mileu. (rupress.org)
  • Here, we show that tumor cells employ DNA-damage-induced nuclear caspase-8 to override the p53-dependent G2/M cell-cycle checkpoint. (bvsalud.org)
  • Illness with LCMV, lacking caspase-8, invokes a high level of cell death considerably reducing cell build up, and maybe this mimics a Capital t cell-tropic computer virus illness that includes a caspase-inhibitory virulence element. (bx-912.com)
  • This plan also includes our work showing that M cell expansion mediated by Tlr3,4, which are the two Tlrs that activate through the adapter Trif, also require caspase-8 for growth. (bx-912.com)
  • How caspases are activated under non-apoptotic conditions and process a selective set of substrates without killing the cell remain enigmatic. (qmul.ac.uk)
  • WB analysis of HT-29 cell lysate in (A) the presence or (B) the absence of blocking peptide using GTX31285 Caspase 8 antibody. (genetex.com)
  • In the intestine, RIPK1 acts as a scaffold to prevent epithelial cell apoptosis and preserve tissue integrity. (uni-koeln.de)
  • FACS analysis and caspase 8 assays demonstrated that CM promoted cell pro-survival trend. (manchester.ac.uk)
  • Upon TNFA stimulation RIPK1 is recruited to a TRADD-TRAF complex initiated by TNFR1 trimerization. (abcam.com)
  • The FLICE/Caspase-8 Colorimetric Assay Kit provides a simple and convenient means for assaying the activity of caspases that recognize the sequence IETD. (genetex.com)
  • RIPK1 is then deubiquitinated and dissociates, forming either complex IIa or IIb. (news-medical.net)
  • Complex IIb, however, is involved in necroptosis and is formed when caspase 8 is inhibited. (news-medical.net)
  • RIPK1 protein is composed of 671 amino acids, and has a molecular weight of about 76 kDa. (wikipedia.org)
  • Caspase-8 antibody was raised against a 15 amino acid synthetic peptide from near the carboxy terminus human caspase-8 isoform E.The immunogen is located within the last 50 amino acids of Caspase-8. (genetex.com)
  • In here, RIPK1 is recruited to the receptors where it is phosphorylated and polyubiquitinated. (wikipedia.org)
  • Kantari C, Walczak H. Caspase-8 and bid: caught in the act between death receptors and mitochondria. (springer.com)
  • Further work revealed that caspase-8 was essential for the induction of the transcription factor "nuclear factor κB" ( NF-κB ) after stimulation through antigen receptors, Fc receptors, or Toll-like receptor 4 in T, B, and natural killer cells . (wikipedia.org)
  • While the critical role of RIPK1 kinase activity in mediating necroptosis and RIPK1-dependent apoptosis has been established, we still know little about how the nonkinase domains of RIPK1 regulate its kinase activity. (pnas.org)