Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The retinoblastoma tumor suppressor protein (RB) has been shown to play a role in regulating the eukaryotic cell cycle, promoting cellular differentiation, and modulating programmed cell death. Although regulation of RB tumor suppressor activity is mediated by reversible phosphorylation, an additional posttranslational modification involves the cleavage of 42 residues from the carboxy terminus of RB during the onset of drug-induced or receptor-mediated apoptosis. We now demonstrate that a recombinant p100cl RB species localizes to the nucleus where it may retain wildtype "pocket" protein binding activity. In addition, using immunocytochemistry, we show that cleavage of the endogenous RB protein occurs in vivo in human cells and that p100cl is predominantly retained within the nuclear compartment of cells during early apoptosis. We also show that the carboxy-terminal cleavage of RB is detected immediately following caspase-3 and PARP cleavage during FAS-mediated apoptosis of MCF10 cells. These findings suggest that this cleavage event may be a component of a downstream cascade during programmed cell death.
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PMID:The 100-kDa proteolytic fragment of RB is retained predominantly within the nuclear compartment of apoptotic cells. 1042 29

We have previously shown that nitric oxide (NO) induces apoptosis in different human neoplastic lymphoid cells through caspase activation. Here we studied the NO-mediated apoptosis in human breast cancer cell lines derived from primary tumor (BT-20) or from metastasis (MCF-7). NO donor glycerol trinitrate (GTN) induced apoptosis in both cell lines which was completely abrogated after pretreatment with the broad spectrum caspase inhibitor zVAD-fmk. NO triggered also a time-dependent activation of caspase-1, caspase-3, and caspase-6 in these cells. Moreover, NO caused a release of mitochondrial protein cytochrome c into the cytosol, an increase in the number of cells with low mitochondrial transmembrane potential and with high level of reactive oxygen species production. However, NO did not induce mRNA expression of CD95 (APO-1/Fas) ligand. FAS-associated phosphatase-1 (FAP-1) molecule was constitutively expressed at the mRNA level and did not show any changes upon NO treatment in both breast cancer cell lines. The expression of the pro-apoptotic protein Bax and of the anti-apoptotic protein Bcl-2 remained unchanged in MCF-7 and BT-20 cells upon GTN treatment. We suggest that the mechanism of NO-mediated activation of the caspase cascade and subsequent apoptosis in human breast cancer cells required mitochondrial damage (in particular, cytochrome c release, disruption of mitochondrial transmembrane potential and generation of reactive oxygen species) but not the activation of the CD95/CD95L pathway.
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PMID:Nitric oxide-mediated apoptosis in human breast cancer cells requires changes in mitochondrial functions and is independent of CD95 (APO-1/Fas). 1060 55

Accelerated apoptosis is one mechanism proposed for the loss of CD4+ T-lymphocytes in human immunodeficiency virus type 1 (HIV-1) infection. The HIV-1 envelope glycoprotein, gp160, contains two C-terminal calmodulin-binding domains. Expression of gp160 in Jurkat T-cells results in increased sensitivity to FAS- and ceramide-mediated apoptosis. The pro-apoptotic effect of gp160 expression is blocked by two calmodulin antagonists, tamoxifen and trifluoperazine. This enhanced apoptosis in response to FAS antibody or C(2)-ceramide is associated with activation of caspase 3, a critical mediator of apoptosis. A point mutation in the C-terminal calmodulin-binding domain of gp160 (alanine 835 to tryptophan, A835W) eliminates gp160-dependent enhanced FAS-mediated apoptosis in transiently transfected cells, as well as in vitro calmodulin binding to a peptide corresponding to the C-terminal calmodulin-binding domain of gp160. Stable Tet-off Jurkat cell lines were developed that inducibly express wild type gp160 or gp160A835W. Increasing expression of wild type gp160, but not gp160A835W, correlates with increased calmodulin levels, increased apoptosis, and caspase 3 activation in response to anti-FAS treatment. The data indicate that gp160-enhanced apoptosis is dependent upon calmodulin up-regulation, involves the activation of caspase 3, and requires calmodulin binding to the C-terminal binding domain of gp160.
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PMID:Requirement of calmodulin binding by HIV-1 gp160 for enhanced FAS-mediated apoptosis. 1062 68

Mutations in the Wiskott-Aldrich syndrome protein (WASP) have been hypothesized to cause defective actin cytoskeletal function. This resultant dysfunction of the actin cytoskeleton has been implicated in the pathogenesis of Wiskott-Aldrich syndrome (WAS). In contrast, it was found that stimulated actin polymerization is kinetically normal in the hematopoietic lineages affected in WAS. It was also found that the actin cytoskeleton in WAS platelets is capable of producing the hallmark cytoarchitectural features associated with activation. Further analysis revealed accelerated cell death in WAS lymphocytes as evidenced by increased caspase-3 activity. This increased activity resulted in accelerated apoptosis of these cells. CD95 expression was also increased in these cells, suggesting an up-regulation in the FAS pathway in WAS lymphocytes. Additionally, inhibition of actin polymerization in lymphocytes using cytochalasin B did not accelerate apoptosis in these cells. This suggests that the accelerated apoptosis observed in WAS lymphocytes was not secondary to an underlying defect in actin polymerization caused by mutation of the WAS gene. These data indicate that WASP does not play a universal role in signaling actin polymerization, but does play a role in delaying cell death. Therefore, the principal consequence of mutations in the WAS gene is to accelerate lymphocyte apoptosis, potentially through up-regulation of the FAS-mediated cell death pathway. This accelerated apoptosis may ultimately give rise to the clinical manifestations observed in WAS. (Blood. 2000;95:1283-1292)
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PMID:Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells. 1066 1

A RIP-like protein, RIP3, has recently been reported that contains an N-terminal kinase domain and a novel C-terminal domain that promotes apoptosis. These experiments further characterize RIP3-mediated apoptosis and NF-kappaB activation. Northern blots indicate that rip3 mRNA displays a restricted pattern of expression including regions of the adult central nervous system. The rip3 gene was localized by fluorescent in situ hybridization to human chromosome 14q11.2, a region frequently altered in several types of neoplasia. RIP3-mediated apoptosis was inhibited by Bcl-2, Bcl-x(L), dominant-negative FADD, as well as the general caspase inhibitor Z-VAD. Further dissection of caspase involvement in RIP3-induced apoptosis indicated inhibition by the more specific inhibitors Z-DEVD (caspase-3, -6, -7, -8, and -10) and Z-VDVAD (caspase-2). However, caspase-1, -6, -8 and -9 inhibitors had little or no effect on RIP3-mediated apoptosis. Mutational analysis of RIP3 revealed that the C-terminus of RIP3 contributed to its apoptotic activity. This region is similar, but distinct, to the death domain found in many pro-apoptotic receptors and adapter proteins, including FAS, FADD, TNFR1, and RIP. Furthermore, point mutations of RIP3 at amino acids conserved among death domains, abrogated its apoptotic activity. RIP3 was localized by immunofluorescence to the mitochondrion and may play a key role in the mitochondrial disruptions often associated with apoptosis.
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PMID:The RIP-like kinase, RIP3, induces apoptosis and NF-kappaB nuclear translocation and localizes to mitochondria. 1081 27

Lymphoma cells often display in vitro resistance to FAS-induced apoptosis, in which caspases act as crucial cell death effectors. Following FAS stimulation, caspase-8 activates caspase-3, which in turn activates the caspase-activated DNAse (CAD) by proteolysis of its inhibitor (ICAD). To investigate the mechanism of FAS resistance, the expression of caspase-8 was analysed by immunohistochemistry, together with that of the substrates caspase-3 and ICAD, in 52 representative samples from non Hodgkin's lymphoma (NHL), 12 from Hodgkin's disease (HD), and eight benign lymphoid tissues. In benign tissues, caspase-8 was co-expressed with caspase-3 in the cytoplasm in germinal centre (GC) cells and was co-expressed with ICAD in the nuclei of the mantle and marginal zone cells. ICAD expression was weak or absent in GC cells. Cytoplasmic staining for both caspase-8 and caspase-3 was present in 11/12 cases of diffuse large cell B-NHL. Caspase-8 positivity was nuclear and cytoplasmic in 9/9 follicular NHLs, in 5/5 mantle cell NHLs and in 6/6 marginal zone NHLs. Five out of six peripheral T-cell NHLs expressed cytoplasmic caspase-8. Ten out of the 12 HD cases lacked significant cytoplasmic staining for caspase-3 and caspase-8 in the majority of Reed-Sternberg cells. All lymphoma cases exhibited predominant nuclear ICAD positivity. Subcellular fractionation analysis of three lymphoma samples and normal mantle zone cells confirmed that ICAD and caspase-8 were at least partly localized in the nucleus. These results show that the profile of caspase-8 expression is correlated with histological lymphoma subtypes; that caspase-8 is co-expressed with caspase-3 in GC cells and their neoplastic counterparts; that ICAD has an immunohistochemical nuclear localization in vivo; and that caspase-8 and ICAD can be co-expressed in the nuclei of mantle zone and marginal zone cells; their unexpected nuclear localization allows a reappraisal of the biochemical cascade of caspase activation.
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PMID:Frequent nuclear localization of ICAD and cytoplasmic co-expression of caspase-8 and caspase-3 in human lymphomas. 1100 95

Respiratory syncytial virus (RSV) infection induced programmed cell death or apoptosis in the cultured lung epithelial cell line, A549. The apoptotic cells underwent multiple changes, including fragmentation and degradation of genomic DNA, consistent with the activation of the DNA fragmentation factor or caspase-activated DNase (DFF or CAD). The infection led to activation of FasL; however, a transdominant mutant of FAS-downstream death domain protein, FADD, did not inhibit apoptosis. Similarly, modest activation of cytoplasmic apoptotic caspases, caspase-3 and -8, were observed; however, only a specific inhibitor of caspases-3 inhibited apoptosis, while an inhibitor of caspase-8 had little effect. No activation of caspase-9 and -10, indicators of the mitochondrial apoptotic pathway, was observed. In contrast, RSV infection strongly activated caspase-12, an endoplasmic reticulum (ER) stress response caspase. Activation of the ER stress response was further evidenced by upregulation of ER chaperones BiP and calnexin. Antisense-mediated inhibition of caspase-12 inhibited apoptosis. Inhibitors of NF-kappa B had no effect on apoptosis. Thus, RSV-induced apoptosis appears to occur through an ER stress response that activates caspase-12, and is uncoupled from NF-kappa B activation.
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PMID:An endoplasmic reticulum-specific stress-activated caspase (caspase-12) is implicated in the apoptosis of A549 epithelial cells by respiratory syncytial virus. 1113 74

The function of BAD, a proapoptotic member of the Bcl-2 family, is regulated primarily by rapid changes in phosphorylation that modulate its protein-protein interactions and subcellular localization. We show here that, during interleukin-3 (IL-3) deprivation-induced apoptosis of 32Dcl3 murine myeloid precursor cells, BAD is cleaved by a caspase(s) at its N terminus to generate a 15-kDa truncated protein. The 15-kDa truncated BAD is a more potent inducer of apoptosis than the wild-type protein, whereas a mutant BAD resistant to caspase 3 cleavage is a weak apoptosis inducer. Truncated BAD is detectable only in the mitochondrial fraction, interacts with BCL-X(L) at least as effectively as the wild-type protein, and is more potent than wild-type BAD in inducing cytochrome c release. Human BAD, which is 43 amino acids shorter than its mouse counterpart, is also cleaved by a caspase(s) upon exposure of Jurkat T cells to anti-FAS antibody, tumor necrosis factor alpha (TNF-alpha), or TRAIL. Moreover, a truncated form of human BAD lacking the N-terminal 28 amino acids is more potent than wild-type BAD in inducing apoptosis. The generation of truncated BAD was blocked by Bcl-2 in IL-3-deprived 32Dcl3 cells but not in Jurkat T cells exposed to anti-FAS antibody, TNF-alpha, or TRAIL. Together, these findings point to a novel and important role for BAD in maintaining the apoptotic phenotype in response to various apoptosis inducers.
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PMID:Caspase cleavage enhances the apoptosis-inducing effects of BAD. 1128 8

The CD95 (FAS, Apo-1) system is a major death pathway in normal and tumor cells. Recent evidence indicates that pancreatic cancer cells express CD95R and CD95L but are insensitive to CD95-mediated apoptosis. Here we show that treatment of human pancreatic cancer cells with RNA synthesis inhibitor actinomycin D (ActD) converted the phenotype of cancer cells from CD95 resistant to CD95 sensitive. Flow cytometric analysis demonstrated that all pancreatic cancer cell lines studied responded with cell surface CD95R and CD95L upregulation to bleomycin treatment, and PANC1 (mt p53) cells demonstrated a dose-dependent response to interferon gamma and bleomycin treatment with CD95R and CD95L up-regulation. However, only bleomycin sensitized PANC1 cells to CD95-mediated apoptosis. Taxol sensitized PANC1 and HPAC cells to CD95-mediated apoptosis without surface up-regulation of CD95R. These data suggest that pancreatic cancer cells possess a p53-independent mechanism of CD95R and CD95L surface upregulation and that surface expression of CD95R is not predictive of apoptotic function. Protein extracts of HPAC and PANC1 cells treated for 24 hours with a combination of ActD/agonist anti-CD95 antibodies demonstrated significantly higher Acetyl-Asp-Glu-Val-Asp-ase (DEVDase) cleavage activity (caspase 3-like activity) than extracts from cells treated with ActD only. In the present study, we also investigated the time kinetics of DEVDase (caspase 3-like) activation in PANC1 (mt p53) and HPAC (wt p53) pancreatic cancer cell lines. We found that DEVDase activity in PANC1 cells responds to ActD and ActD/anti-CD95 antibodies earlier than in HPAC cells; however, at 24 hours HPAC cells demonstrated much stronger activation. Cytosolic protein extracts from untreated cells did not influence caspase 3-like activity when added to extracts from the ActD/anti-CD95 antibody-treated cells. Collectively, these data suggest that pancreatic cancer cells have functional CD95-related apoptotic machinery with preserved apoptotic signal transduction, CD95R upregulation. and caspase activation. However, this system is blocked by some unknown protein(s) that is either located in the organelle fraction of the cell and/or requires an intact cell for manifestation of its activity.
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PMID:CD95-related apoptotic machinery is functional in pancreatic cancer cells. 1134 35

The mechanisms by which bile acids induce apoptosis in hepatocytes and the signaling pathways involved in the control of cell death are not understood fully. Here, we examined the impact of mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3-kinase (PI3K) signaling on the survival of primary hepatocytes exposed to bile acids. Treatment of hepatocytes with deoxycholic acid (DCA), chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA) caused sustained MAPK activation that was dependent on activation of the epidermal growth factor receptor (EGFR). Activation of MAPK was partially blocked by inhibitors of PI3K. Inhibition of DCA-, CDCA-, and UDCA-stimulated MAPK activation resulted in approximately 20%, approximately 35%, and approximately 55% apoptosis, respectively. The potentiation of DCA- and CDCA-induced apoptosis by MEK1/2 inhibitors correlated with cleavage of procaspase 3, which was blocked by inhibitors of caspase 8 (ile-Glu-Thr-Asp-p-nitroanilide [IETD]) and caspase 3 (DEVD). In contrast, the potentiation of UDCA-induced apoptosis weakly correlated with procaspase 3 cleavage, yet this effect was also blocked by IETD and DEVD. Incubation of hepatocytes with the serine protease inhibitor AEBSF reduced the death response of cells treated with UDCA and MEK1/2 inhibitor to that observed for DCA and MEK1/2 inhibitor. The apoptotic response was FAS receptor- and neutral sphingomyelinase-dependent and independent of FAS ligand expression, and neither chelation of intracellular and extracellular Ca(2+) nor down-regulation of PKC expression altered the apoptotic effects of bile acids. In conclusion, bile acid apoptosis is dependent on the production of ceramide and is counteracted by activation of the MAPK and PI3K pathways.
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PMID:Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes. 1191 48


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