Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synovial T cells in rheumatoid arthritis are highly differentiated and express a phenotype suggesting susceptibility to apoptosis (CD45RB dull, CD45RO bright, Bcl-2 low, Bax high, Fas high). However, no evidence of T cell apoptosis was found in synovial fluid from any of 28 patients studied. In contrast, synovial fluid from 10 patients with crystal arthritis showed substantial levels of T cell apoptosis. The failre of apoptosis was not an intrinsic property of rheumatoid synovial T cells, as they showed rapid spontaneous apoptosis on removal from the joint. Synovial T cells from rheumatoid arthritis and gout patients could be rescued from spontaneous apoptosis in vitro either by IL-2R gamma chain signaling cytokines (which upregulate Bcl-2 and Bcl-XL) or by interaction with synovial fibroblasts (which upregulates Bcl-xL but not Bcl-2). The phenotype of rheumatoid synovial T cells ex vivo (Bcl-2 low, Bcl-xL high) suggested a fibroblast-mediated mechanism in vivo. This was confirmed by in vitro culture of synovial T cells with fibroblasts which maintained the Bcl-xL high Bcl-2 low phenotype. Synovial T cells from gout patients were Bcl-2 low Bcl-xL low and showed clear evidence of apoptosis in vivo. Inhibition experiments suggested that an integrin-ligand interaction incorporating the Arg-Gly-Asp motif is involved in fibroblast-mediated synovial T cell survival. We propose that environmental blockade of cell death resulting from interaction with stromal cells is a major factor in the persistent T cell infiltration of chronically inflamed rheumatoid synovium.
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PMID:Inhibition of T cell apoptosis in the rheumatoid synovium. 902 77

Although histological data suggest that cholangiocytes die by apoptosis in human liver diseases, no information exists on the mechanisms of cholangiocyte apoptosis. Thus our aims were to establish an in vitro model of cholangiocyte apoptosis and to test the hypothesis that changes in intracellular ions would cause apoptosis in cholangiocytes by a protease-sensitive pathway. A large number of proapoptotic agents were ineffective in inducing apoptosis in rat or human cholangiocytes in culture; in contrast, beauvericin, a K+ ionophore, caused apoptosis in both cell lines, despite their expression of Bcl-2. Although beauvericin decreased intracellular K+ and increased intracellular Ca2+, abolishing the K+ gradient did not prevent beauvericin-induced apoptosis; in contrast, omission of extracellular Ca2+ inhibited apoptosis by 42%. The interleukin-1 beta-converting enzyme (ICE) family protease inhibitor, Z-Val-Ala-Asp chloromethylketone, inhibited apoptosis in a concentration-dependent manner. By Northern blot analysis, cholangiocytes expressed the mRNA for three members of the ICE protease family: ICE, ICE/ CED-3 homologue-1 (ICH-1), and cysteine protease P-32 (CPP-32). Cleavage of a substrate for CPP-32-like protease activity, but not a substrate for ICE and ICH-1, increased after beauvericin treatment. In summary, we have established an in vitro model of apoptosis in cholangiocytes. Our data suggest that beauvericin-induced apoptosis occurs by a Ca(2+)-dependent CPP-32 protease-sensitive pathway despite cholangiocyte expression of Bcl-2.
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PMID:Development and initial application of an in vitro model of apoptosis in rodent cholangiocytes. 903 83

In the granule exocytosis pathway of cell-mediated cytotoxicity, rapid apoptotic nuclear damage in target cells has been unequivocally linked to granzyme B activity. Direct cleavage and activation of caspase-3 and related proteases by granzyme B have been identified as a central event in apoptosis induction by cytotoxic granules. The Bcl-2 oncoprotein has been recently shown to act at the level or upstream of caspase-3 family activation to inhibit apoptosis induced by various stimuli including Fas ligation, an alternative cell-mediated lytic pathway. In this study, we have investigated whether activation of this caspase family by granzyme B, during human NK and lymphokine-activated killer cell granule-mediated apoptosis, could be influenced by Bcl-2 expression. Bcl-2-overexpressing clones were generated from parental K562 and U937 cell lines (K6 and U4 clones, respectively). Bcl-2 expression abrogated early 125I-DNA release and DNA fragmentation, these defects being compensated for by extended incubation times. Cleavage of poly(ADP-ribose) polymerase, a specific caspase-3 family substrate, was detected in parental K562 cells exposed to lymphokine-activated killer effectors but not in K6 targets, indicating that caspase-3 and related proteases function was inhibited by Bcl-2. Functional inhibition of caspase-3 family with benzyloxycarbonyl-Asp-Glu-Val-Asp(OMe) fluoromethylketone led to similar consequences on apoptotic nuclear events as for Bcl-2 expression. Thus, Bcl-2 antagonizes granzyme B-mediated apoptosis by a mechanism that interferes with caspase-3 activity. Finally, Bcl-2 expression or the Asp-Glu-Val-Asp peptide was much less efficient in preventing phosphatidylserine externalization, suggesting that despite impaired nuclear apoptosis, immediate recognition and elimination of Bcl-2-expressing cells by tissue phagocytes should remain partly unaffected.
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PMID:Bcl-2 expression in target cells leads to functional inhibition of caspase-3 protease family in human NK and lymphokine-activated killer cell granule-mediated apoptosis. 920 Apr 47

Dissociated cerebellar granule cells maintained in medium containing 25 mM potassium undergo an apoptotic death when switched to medium with 5 mM potassium. Granule cells from mice in which Bax, a proapoptotic Bcl-2 family member, had been deleted, did not undergo apoptosis in 5 mM potassium, yet did undergo an excitotoxic cell death in response to stimulation with 30 or 100 microM NMDA. Within 2 h after switching to 5 mM K+, both wild-type and Bax-deficient granule cells decreased glucose uptake to <20% of control. Protein synthesis also decreased rapidly in both wild-type and Bax-deficient granule cells to 50% of control within 12 h after switching to 5 mM potassium. Both wild-type and Bax -/- neurons increased mRNA levels of c-jun, and caspase 3 (CPP32) and increased phosphorylation of the transactivation domain of c-Jun after K+ deprivation. Wild-type granule cells in 5 mM K+ increased cleavage of DEVD-aminomethylcoumarin (DEVD-AMC), a fluorogenic substrate for caspases 2, 3, and 7; in contrast, Bax-deficient granule cells did not cleave DEVD-AMC. These results place BAX downstream of metabolic changes, changes in mRNA levels, and increased phosphorylation of c-Jun, yet upstream of the activation of caspases and indicate that BAX is required for apoptotic, but not excitotoxic, cell death. In wild-type cells, Boc-Asp-FMK and ZVAD-FMK, general inhibitors of caspases, blocked cleavage of DEVD-AMC and blocked the increase in TdT-mediated dUTP nick end labeling (TUNEL) positivity. However, these inhibitors had only a marginal effect on preventing cell death, suggesting a caspase-independent death pathway downstream of BAX in cerebellar granule cells.
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PMID:Bax deletion further orders the cell death pathway in cerebellar granule cells and suggests a caspase-independent pathway to cell death. 931 40

In the A20 cell line, we examined the mechanisms that modulate the Fas-mediated apoptotic pathway through the B cell receptor. As in other systems, Fas signaling activates cysteine proteases, leading to specific proteolysis of poly(ADP-ribose) polymerase (PARP) and protein kinase C (PKC) delta. We describe that PKC-epsilon and PKC-zeta proteins are two new IL-1 beta-converting enzyme (ICE) substrates; we found that ICE activation and its proteolytic effects are inhibited by surface IgG (sIgG) cross-linking. Apoptosis induced by Fas ligation is consequently abrogated after sIgG engagement, and sIgG signaling therefore interferes with the apoptotic signal upstream of ICE protease activation. Since the PKC inhibitor bisindolylmaleimide I completely abolishes the protective effect of the sIgG signal, a member of the PKC family is probably responsible for the prevention of ICE cascade activation. Direct activation of PKC by PMA partially mimics the protective effect of sIgG cross-linking against Fas-mediated death in A20 cells. Nevertheless, PMA inhibits neither ICE activation nor the subsequent proteolysis of ICE substrates, suggesting that the PKC responsible for ICE inactivation is a non-PMA-sensitive PKC. In this system, Fas ligation also triggers Bcl-2/Bcl-x down-regulation, an effect inhibited by sIgG cross-linking, the cysteine protease inhibitor acetyl-Tyr-Val-Ala-Asp-chloromethyl ketone, and PMA treatment. In A20 cells, Fas signaling may thus trigger both ICE activation and Bcl-x and Bcl-2 down-regulation. These results indicate that sIgG signaling gives rise to two pathways after PKC activation, one presumably promoted by non-PMA-sensitive PKC, which inactivates the ICE cascade, and another produced by PMA-sensitive PKC, which maintains normal Bcl-2/Bcl-x levels.
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PMID:B cell receptor cross-linking prevents Fas-induced cell death by inactivating the IL-1 beta-converting enzyme protease and regulating Bcl-2/Bcl-x expression. 931 14

Betulinic acid (BA), a melanoma-specific cytotoxic agent, induced apoptosis in neuroectodermal tumors, such as neuroblastoma, medulloblastoma, and Ewing's sarcoma, representing the most common solid tumors of childhood. BA triggered an apoptosis pathway different from the one previously identified for standard chemotherapeutic drugs. BA-induced apoptosis was independent of CD95-ligand/receptor interaction and accumulation of wild-type p53 protein, but it critically depended on activation of caspases (interleukin 1beta-converting enzyme/Ced-3-like proteases). FLICE/MACH (caspase-8), considered to be an upstream protease in the caspase cascade, and the downstream caspase CPP32/YAMA/Apopain (caspase-3) were activated, resulting in cleavage of the prototype substrate of caspases PARP. The broad-spectrum peptide inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cleavage of FLICE and PARP, also completely abrogated BA-triggered apoptosis. Cleavage of caspases was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species. Overexpression of Bcl-2 and Bcl-XL conferred resistance to BA at the level of mitochondrial dysfunction, protease activation, and nuclear fragmentation. This suggested that mitochondrial alterations were involved in BA-induced activation of caspases. Furthermore, Bax and Bcl-xs, two death-promoting proteins of the Bcl-2 family, were up-regulated following BA treatment. Most importantly, neuroblastoma cells resistant to CD95- and doxorubicin-mediated apoptosis were sensitive to treatment with BA, suggesting that BA may bypass some forms of drug resistance. Because BA exhibited significant antitumor activity on patients' derived neuroblastoma cells ex vivo, BA may be a promising new agent for the treatment of neuroectodermal tumors in vivo.
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PMID:Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors. 986 49

Bcl-2 family proteins and ICE/CED-3 family proteases (caspases) are regarded as the basic regulators of apoptotic cell death. They are evolutionarily conserved and implicated in a variety of apoptosis. However, the precise mechanism by which these two families interact to regulate cell death is not yet known. In this study, we found that the overexpression of the Bcl-2 family member Bax induced apoptotic cell death in COS-7 cells through the activation of CPP32 (caspase-3)-like proteases that cleaved the DEVD tetrapeptide. This apoptotic cell death was suppressed by the viral proteins CrmA and p35, as well as by the chemically synthesized caspase inhibitors Z-Asp-CH2-DCB and zVAD-fmk. We also found that the Bax-induced apoptosis of COS-7 cells was suppressed by Bcl-xL and Bcl-2, though both Bcl-xL and Bcl-2 similarly prevented etoposide-induced apoptosis in COS-7 cells. In addition, Bcl-xL inhibited the activation of caspase-3-like proteases accompanying Bax-induced COS-7 cell death but Bcl-2 did not. These results indicate that the caspase activation is essential for Bax-induced apoptosis, and that the ability of Bcl-2 and Bcl-xL to prevent the Bax-induced caspase activation and apoptosis in COS-7 cells could be differentially regulated. Our results also suggest that Bcl-2 family proteins function upstream of caspase activation and control apoptosis through the regulation of caspase activity.
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PMID:Caspase-dependent apoptosis of COS-7 cells induced by Bax overexpression: differential effects of Bcl-2 and Bcl-xL on Bax-induced caspase activation and apoptosis. 936 42

Upon treatment with NO-releasing compounds such as S-nitrosoglutathione or spermine NO, human myeloid leukemia U937 cells undergo apoptosis. Early NO-mediated signals comprise activation of a Z-A-DCB (benzoyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene)-sensit ive, caspase-3 like cysteine protease that cleaved poly (ADP-ribose) polymerase (PARP), U1 small nuclear ribonucleoprotein (U1 snRNP), and the fluorogenic substrate N-acetyl-Asp-Glu-Val-Asp-7-amido-4-methylcoumarin. In association with these early apoptotic alterations p21 (WAF1/Cip1) is upregulated, but NO affected cell proliferation and apoptosis at a similar dose. At later time points the classical antiapoptotic protein Bcl-2 is downregulated, indicating that decreased Bcl-2 expression is secondary and not a prerequisite for initiation of apoptosis. N-Acetylcysteine (1 mM) interfered with NO-mediated apoptotic signaling, blocking DNA fragmentation as well as PARP and U1 snRNP cleavage. In contrast Z-A-DCB suppressed DNA fragmentation and U1 snRNP cleavage, while PARP breakdown proceeded unaltered. Observing proteolytic PARP digestion without apoptotic alterations questions PARP cleavage as an apoptotic parameter. These results suggest that a Z-A-DCB-sensitive caspase that is distinct from the PARP-cleaving enzyme is activated during NO exposure. NO-mediated apoptotic signaling in U937 cells activates caspases, some of which are dispensable for propagating the death signal.
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PMID:U937 apoptotic cell death by nitric oxide: Bcl-2 downregulation and caspase activation. 945 54

Apoptosis requires the activation of caspases (formerly interleukin 1beta-converting enzyme-like proteases), in particular those related to the caspase-3/7/6 subfamily. Recent data, however, revealed that, although caspase-specific inhibitors delay apoptosis, they are often incapable of preventing it. To obtain evidence for caspase-independent steps of apoptosis, we artificially created a high amount of short-lived or aberrant proteins by blocking the ubiquitin degradation pathway. A temperature-sensitive defect in the ubiquitin-activating enzyme E1 induced apoptosis independent of the activation of caspase-3 and -6 and the cleavage of their respective substrates poly(ADP-ribose) polymerase and lamin A. In addition, neither the caspase 3/7-specific inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone nor the general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone were capable of blocking this type of cell death. By contrast, Bcl-2 overexpression effectively protected cells from apoptosis induced by a defect in the E1 enzyme at the nonpermissive temperature. Bcl-2 acted downstream of the accumulation of short-lived or aberrant proteins because it did not prevent the overexpression of the short-lived proteins p53, p27(kip1), and cyclins D1 and B1 under conditions of decreased ubiquitination. These results suggest the existence of short-lived proteins that may serve the role of caspase-independent effectors of apoptosis and attractive targets of the death-protective action of Bcl-2.
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PMID:Defects in the ubiquitin pathway induce caspase-independent apoptosis blocked by Bcl-2. 949 30

Recent evidence suggests that untimely retinoblastoma protein (RB) dephosphorylation and/or proteolytic degradation might provide key events down-stream cysteine protease (caspase) activation in apoptosis induction. We have dealt with this issue by studying apoptosis induced by N-hexanoylsphingosine (C6-Cer) in CHP-100 human neuroepithelioma cells, maintained in complete growth medium. We report that C6-Cer-induced apoptosis occurred predominantly in G1/S phases of the cycle and was associated with RB dephosphorylation, in the setting of negligible Bcl-2 expression. Apoptosis was also associated with poly(ADP-ribose) polymerase (PARP) cleavage, thus indicating activation of CPP32/Yama/apopain (caspase-3); however, while the tripeptide caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethylketone was able to prevent both C6-Cer-induced PARP cleavage and apoptosis, it was ineffective in preventing RB dephosphorylation. Moreover proteolytic RB cleavage occurred only to a marginal extent after C6-Cer treatment. These results indicate that apoptosis induced by ceramide in CHP-100 cells is caspase-mediated, but RB post-translational modification does not provide a key step, downstream caspase activation, in apoptosis execution.
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PMID:Ceramide-induced apoptosis is mediated by caspase activation independently from retinoblastoma protein post-translational modification. 950 Oct 10


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