Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.62 (caspase-9)
7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis requires recruitment of caspases by receptor-associated adaptors through homophilic interactions between the CARDs (caspase recruitment domains) of adaptor proteins and prodomains of caspases. We have solved the CARD structure of the RAIDD adaptor protein that recruits ICH-1/caspase-2. It consists of six tightly packed helices arranged in a topology homologous to the Fas death domain. The surface contains a basic and an acidic patch on opposite sides. This polarity is conserved in the ICH-1 CARD as indicated by homology modeling. Mutagenesis data suggest that these patches mediate CARD/CARD interaction between RAIDD and ICH-1. Subsequent modeling of the CARDs of Apaf-1 and caspase-9, as well as Ced-4 and Ced-3, showed that the basic/acidic surface polarity is highly conserved, suggesting a general mode for CARD/CARD interaction.
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PMID:Solution structure of the RAIDD CARD and model for CARD/CARD interaction in caspase-2 and caspase-9 recruitment. 969 46

Although cardiomyocyte (CM) apoptosis has been well described in both in vitro and in vivo models of ischemic heart disease, the intracellular pathways leading to CM death have not been fully characterized. To define the role of death receptor signaling in CM apoptosis, we constructed recombinant adenoviral vectors carrying wild-type (wt) or dominant negative (dn) forms of the death receptor adaptor protein FADD (Fas-associated death domain protein) and used these vectors to transduce rat neonatal CMs in models of hypoxia- and serum deprivation (SD)-induced apoptosis. The combination of SD and hypoxia induced rapid activation of caspase-3 and -8 as well as DNA fragmentation, reaching a plateau within 4-8 h. Adenoviral expression of FADD-dn inhibited caspase-8 activation as well as hypoxia/SD-induced apoptosis at 24 h in an moi (multiplicity of infection)-dependent manner. In contrast, adenoviral expression of FADD-wt increased apoptosis and caspase-3 activity in CMs under both normoxic and hypoxic conditions. Surprisingly, FADD-dn, as well as the specific caspase-8 inhibitor benzyloxycarbonyl-IETD-fluoromethylketone also inhibited the activation of caspase-9 and -3 in CMs subjected to hypoxia/SD. These data suggest a primary role for FADD/caspase-8 signaling that is necessary and sufficient for apoptosis of CMs subjected to hypoxia/SD.
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PMID:Importance of FADD signaling in serum deprivation- and hypoxia-induced cardiomyocyte apoptosis. 1206 58

Upon engagement with Fas ligand (FasL), Fas rapidly induces recruitment and self-processing of caspase-8 via the adaptor protein Fas-associated death domain (FADD), and activated caspase-8 cleaves downstream substrates such as caspase-3. We have found that penicillic acid (PCA) inhibits FasL-induced apoptosis and concomitant loss of cell viability in Burkitt's lymphoma Raji cells. PCA prevented activation of caspase-8 and caspase-3 upon treatment with FasL. However, PCA did not affect active caspase-3 in FasL-treated cells, suggesting that PCA primarily blocks early signaling events upstream of caspase-8 activation. FasL-induced processing of caspase-8 was severely impaired in the death-inducing signaling complex, although FasL-induced recruitment of FADD and caspase-8 occurred normally in PCA-treated cells. Although PCA inhibited the enzymatic activities of active recombinant caspase-3, caspase-8, and caspase-9 at similar concentrations, PCA exerted weak inhibitory effects on activation of caspase-9 and caspase-3 in staurosporine-treated cells but strongly inhibited caspase-8 activation in FasL-treated cells. Glutathione and cysteine neutralized an inhibitory effect of PCA on caspase-8, and PCA bound directly to the active center cysteine in the large subunit of caspase-8. Thus, our present results demonstrate that PCA inhibits FasL-induced apoptosis by targeting self-processing of caspase-8.
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PMID:The mycotoxin penicillic acid inhibits Fas ligand-induced apoptosis by blocking self-processing of caspase-8 in death-inducing signaling complex. 1248 80

Proteolytic activation of initiator procaspases is a crucial step in the cellular commitment to apoptosis. Alternative models have been postulated for the activation mechanism, namely the oligomerization or induced proximity model and the allosteric regulation model. While the former holds that procaspases become activated upon proper oligomerization by an adaptor protein, the latter states that the adaptor is an allosteric regulator for procaspases. The allosteric regulation model has been applied for the activation of procaspase-9 by apoptotic protease-activating factor (Apaf-1) in an oligomeric complex known as the apoptosome. Using approaches that allow for controlled oligomerization, we show here that aggregation of multiple procaspase-9 molecules can induce their activation independent of the apoptosome. Oligomerization-induced procaspase-9 activation, both within the apoptosome and in artificial systems, requires stable homophilic association of the protease domains, raising the possibility that the function of Apaf-1 is not only to oligomerize procaspase-9 but also to maintain the interaction of the caspase-9 protease domain after processing. In addition, we provide biochemical evidence that other apoptosis initiator caspases (caspase-2 and -10) as well as a procaspase involved in inflammation (murine caspase-11) are also activated by oligomerization. Thus, oligomerization of precursor molecules appears to be a general mechanism for the activation of both apoptosis initiator and inflammatory procaspases.
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PMID:Oligomerization is a general mechanism for the activation of apoptosis initiator and inflammatory procaspases. 1263 14

The apoptosis-associated speck-like protein (ASC) is an unusual adaptor protein that contains the Pyrin/PAAD death domain in addition to the CARD protein-protein interaction domain. Here, we present evidence that ASC can function as an adaptor molecule for Bax and regulate a p53-Bax mitochondrial pathway of apoptosis. When ectopically expressed, ASC interacted directly with Bax, colocalized with Bax to the mitochondria, induced cytochrome c release with a significant reduction of mitochondrial membrane potential and resulted in the activation of caspase-9, -2 and -3. The rapid induction of apoptosis by ASC was not observed in Bax-deficient cells. We also show that induction of ASC after exposure to genotoxic stress is dependent on p53. Blocking of endogenous ASC expression by small-interfering RNA (siRNA) reduced the apoptotic response and inhibited translocation of Bax to mitochondria in response to p53 or genotoxic insult, suggesting that ASC is required to translocate Bax to the mitochondria. Our findings demonstrate that ASC has an essential role in the intrinsic mitochondrial pathway of apoptosis through a p53-Bax network.
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PMID:ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. 1473 Mar 12

Apoptosis is triggered by activation of initiator caspases upon complex-mediated clustering of the inactive zymogen, as occurs in the caspase-9-activating apoptosome complex. Likewise, caspase-2, which is involved in stress-induced apoptosis, is recruited into a large protein complex, the molecular composition of which remains elusive. We show that activation of caspase-2 occurs in a complex that contains the death domain-containing protein PIDD, whose expression is induced by p53, and the adaptor protein RAIDD. Increased PIDD expression resulted in spontaneous activation of caspase-2 and sensitization to apoptosis by genotoxic stimuli. Because PIDD functions in p53-mediated apoptosis, the complex assembled by PIDD and caspase-2 is likely to regulate apoptosis induced by genotoxins.
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PMID:The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. 1507 21

Tri-n-butyltin (TBT), a biocide, is known for its immunotoxicity and hepatotoxicity and is a well-characterised mitochondrial toxin. This report investigates the mechanisms involved in induction of apoptosis by TBT in primary cultures of rat hepatocytes. Release of cytochrome c from mitochondria into the cytosol was apparent after 15 min of exposure to 2.5 microM TBT. In addition, activity of initiator caspase-9 increased after 30 min, representing activation of the mitochondrial pathway in hepatocytes. The death receptor pathway was also activated by TBT, as indicated by recruitment of the adaptor protein FADD from the cytosol to the membrane as soon as 15 min after treatment. In addition, levels of the pro-apoptotic protein Bid decreased in the cytosol, while there was an increase in levels of the cleaved form tBid, in TBT-treated hepatocytes. Activity of initiator caspase-8 increased after 30 min. The principal effector caspase-3 was activated following 30 min of treatment with TBT. Activation was confirmed by immunodetection of a 17-kDa cleaved fragment. Apoptotic substrates such as Poly(ADP-ribose) polymerase and DNA fragmentation factor-45 are cleaved by caspase-3 to ensure the dismantlement of the cell. Cleavage of Poly(ADP-ribose) polymerase into a 85-kDa fragment appeared after 30 min of TBT treatment. DNA fragmentation factor-45 disappeared in TBT-exposed rat hepatocytes. This is the first detailed study reporting the involvement of initiator and effector caspases, cleavage of their intracellular substrates and activation of both death receptor and mitochondrial pathways in TBT-induced apoptosis in rat hepatocytes. The comprehension of molecular events of apoptosis is important for the evaluation of the risk to humans and animals.
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PMID:Involvement of mitochondrial and death receptor pathways in tributyltin-induced apoptosis in rat hepatocytes. 1527 21

More than 99% of follicles undergo a degenerative process known as "atresia", in mammalian ovaries, and only a few follicles ovulate during ovarian follicular development. We have investigated the molecular mechanism of selective follicular atresia in mammalian ovaries, and have reported that follicular selection dominantly depends on granulosa cell apoptosis. However, we have little knowledge of the molecular mechanisms that control apoptotic cell death in granulosa cells during follicle selection. To date, at least five cell death ligand-receptor systems [tumor necrosis factor (TNF)alpha and receptors, Fas (also called APO-1/CD95) ligand and receptors, TNF-related apoptosis-inducing ligand (TRAIL; also called APO-2) and receptors, APO-3 ligand and receptors, and PFG-5 ligand and receptors] have been reported in granulosa cells of porcine ovaries. Some cell death ligand-receptor systems have "decoy" receptors, which act as inhibitors of cell death ligand-induced apoptosis in granulosa cells. Moreover, we showed that the porcine granulosa cell is a type II apoptotic cell, which has the mitochondrion-dependent apoptosis-signaling pathway. Briefly, the cell death receptor-mediated apoptosis signaling pathway in granulosa cells has been suggested to be as follows. (1) A cell death ligand binds to the extracellular domain of a cell death receptor, which contains an intracellular death domain (DD). (2) The intracellular DD of the cell death receptor interacts with the DD of the adaptor protein (Fas-associated death domain: FADD) through a homophilic DD interaction. (3) FADD activates an initiator caspase (procaspase-8; also called FLICE), which is a bipartite molecule, containing an N-terminal death effector domain (DED) and a C-terminal DD. (4) Procaspase-8 begins auto-proteolytic cleavage and activation. (5) The auto-activated caspase-8 cleaves Bid protein. (6) The truncated Bid releases cytochrome c from mitochondrion. (7) Cytochrome c and ATP-dependent oligimerization of apoptotic protease-activating factor-1 (Apaf-1) allows recruitment of procaspase-9 into the apoptosome complex. Activation of procaspase-9 is mediated by means of a conformational change. (8) The activated caspase-9 cleaves downstream effector caspases (caspase-3). (9) Finally, apoptosis is induced. Recently, we found two intracellular inhibitor proteins [cellular FLICE-like inhibitory protein short form (cFLIPS) and long form (cFLIPL)], which were strongly expressed in granulosa cells, and they may act as anti-apoptotic/survival factors. Further in vivo and in vitro studies will elucidate the largely unknown molecular mechanisms, e. g. which cell death ligand-receptor system is the dominant factor controlling the granulosa cell apoptosis of selective follicular atresia in mammalian ovaries. If we could elucidate the molecular mechanism of granulosa cell apoptosis (follicular selection), we could accurately diagnose the healthy ovulating follicles and precisely evaluate the oocyte quality. We hope that the mechanism will be clarified and lead to an integrated understanding of the regulation mechanism.
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PMID:Regulation mechanism of selective atresia in porcine follicles: regulation of granulosa cell apoptosis during atresia. 1551 56

Apoptotic cell death is executed by a family of cysteine proteases known as caspases. Synthesized as inactive precursors, caspases become activated sequentially in cascades. Activation of apical or initiator caspases in these cascades occurs in macromolecular complexes located in various compartments. One such complex is the plasma membrane-bound death-inducing signaling complex (DISC), formed upon engagement of death receptors, which recruits and activates caspase-8 and -10. Another complex is the cytosolic apoptosome, assembled in response to the release of mitochondrial cytochrome c, which recruits caspase-9. The other major human initiator caspase is caspase-2, which is activated in response to various lethal stimuli and has recently been shown to be required for DNA damage-induced apoptosis. The regulation of caspase-2 is not well understood. Here we present evidence that caspase-2 is localized to the promyelocytic leukemia protein nuclear bodies (PML-NBs), nuclear macro-molecular complexes that are involved in many scenarios of apoptosis including DNA damage. The localization of caspase-2 requires both the prodomain and protease domain but appears to be independent of its adaptor protein, CRADD/RAIDD. These data suggest the existence of a nuclear apoptosis pathway that involves both caspase-2 and the PML-NBs.
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PMID:Association of caspase-2 with the promyelocytic leukemia protein nuclear bodies. 1591 62

Rupture-prone unstable arterial plaques develop concomitantly with the appearance of intraplaque hemorrhage and tissue ulceration, in association with deregulation of smooth muscle cell mitogenesis and leakage of newly formed blood vessels. Using microarray technology, we have identified novel protein deregulation associated with unstable carotid plaque regions. Overexpression of proapoptotic proteins caspase-9 and TRAF4 was seen in endothelial cells and smooth muscle cells from unstable hemorrhagic and ulcerated plaque regions. Topoisomerase-II-alpha (TOPO-II-alpha), which is associated with DNA repair mechanisms, was also overexpressed by these cells. Cell signaling molecules c-src, G-protein-coupled receptor kinase-interacting protein (GIT1), and c-jun N-terminal kinase (JNK) were up-regulated in endothelial cells from the same areas, whereas an increase in expression of junctional adhesion molecule-1 (JAM-1) in blood vessels and infiltrating macrophages from inflammatory regions might form part of a leukocyte rolling response, increasing the plaque volume. Grb2-like adaptor protein (Gads), responsible for differentiation of monocytes into macrophages, was expressed by macrophages from unstable plaques, suggesting a potential mechanism through which increased scavenging could occur in rupture-prone areas. We conclude that modulation of novel cell signaling intermediates, such as those described here, could be useful in the therapy of angiogenesis and apoptosis, designed to reduce unstable plaque formation.
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PMID:Identification of differential protein expression associated with development of unstable human carotid plaques. 1650 14


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