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)

We have defined an in vitro model for the study of microvascular endothelial cell (EC) apoptosis mediated by plasma from patients with various forms of thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). This system reproduces a variety of histopathologic and ultrastructural features of tissue EC involved in TTP/sporadic HUS, suggesting that apoptotic EC injury is a primary pathophysiologic event in the thrombotic microangiopathies. We now document the ability of tetrapeptide-based inhibitors of interleukin 1beta-converting enzyme (ICE)-like caspase 1 and cysteine protease protein (CPP)-32-like caspase 3, two members of a novel class of cysteine proteases involved in final pathways to apoptosis, to block TTP/sporadic HUS plasma-mediated apoptosis. Overexpression of Bcl-X(L) via gene transfer suppressed this apoptosis by 70%. Transduction of EC with the Bcl-2 homolog A1 had a more limited protective effect. These findings support a role for apoptosis-linked cysteine proteases in the pathophysiology of TTP and sporadic HUS, and raise the possibility that specific apoptosis inhibitors may have a role in the experimental therapeutics of these syndromes.
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PMID:Role of caspases 1 and 3 and Bcl-2-related molecules in endothelial cell apoptosis associated with thrombotic microangiopathies. 984 Sep 8

The Tpl-2 kinase activates the nuclear factor of activated T cells (NFAT) and induces IL-2 expression in T-cell lines. Here we show that the activation of the IL-2 promoter by Tpl-2 is inhibited by mutant signaling molecules that inhibit the mitogen-activated protein kinase (MAPK) or the calcineurin/NFAT pathways and is promoted by combinations of signaling molecules that activate these pathways. We, therefore, conclude that signals generated by the convergence of the MAPK and the calcineurin/NFAT pathway are necessary and sufficient for the activation of the IL-2 promoter by Tpl-2. The activation of both the IL-2 promoter and an NFAT-driven minimal promoter were shown to depend on signals transduced by Raf1. However, it was only the IL-2 promoter whose activation by Tpl-2 was fully blocked by the dominant negative mutant MEK1S218/222A and the MEK1/MEK2 inhibitor PD098059. Since the activation of NFAT is MAPK-dependent these findings suggested that the activation of MAPK by Tpl-2 is either independent or only partially dependent on MEK1 and MEK2. In addition, they suggested that the activation of the IL-2 promoter is under the control of not only NFAT but also a second factor whose activation is MEK-dependent. Experiments in COS-1 and EL-4 cells confirmed both hypotheses and revealed that the second factor activated by Tpl-2 is NF-kappaB. While the activation of the IL-2 promoter and an NFAT-driven minimal promoter by Tpl-2 was fully blocked by the dominant negative mutant NFAT delta418, it was only partially blocked by the calcineurin inhibitor cyclosporin A suggesting that the Tpl-2-mediated NFAT activation is under the control of a combination of calcineurin-dependent and independent pathways. Both pathways were fully blocked by Bcl-2 or Bcl-X(L).
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PMID:Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-kappaB. 984 Sep 24

The present study retrospectively examines the correlation between the outcome of patients with locally advanced esophageal squamous cell carcinoma (LAEC) after multimodal treatment (radiochemotherapy +/- surgery) and the expression of apoptosis-regulating proteins in pretherapeutic biopsies. Thirty-eight patients with LAEC who took part in a prospective multicentric trial received radiochemotherapy, optionally followed by surgery. Pretreatment tumor biopsies were immunohistochemically investigated for expression of p53, Bcl-2, Bax (bcl-2-associated X protein), and Bcl-X(L) (bcl-2-related X protein). The overall expression of p53, Bcl-2, Bax, and Bcl-X(L) was 52.6, 57.9, 100, and 97.4% respectively. Tumors without p53 expression and tumors with weak Bcl-X(L) expression showed response to chemotherapy more frequently (55.6 and 52.6%, respectively) than tumors positive for p53 expression and tumors with strong Bcl-X(L) expression (30.0 and 31.6%, respectively); however, these differences did not attain statistical significance. No correlations were found between the expression of Bcl-2 and Bax and the response to chemotherapy. In patients treated by radiochemotherapy and surgery, p53-negative tumors showed a significantly better outcome than p53-positive tumors (mean survival, 31.1 months versus 11.3 months; P = 0.0378). Additionally, a more favorable outcome was observed in tumors positive for Bcl-2 (not significant), whereas no differences in survival were observed in relation to the expression of Bax or Bcl-X(L). No differences in survival were observed in patients treated by radiochemotherapy without subsequent resection therapy in relation to the expression of apoptosis-regulating proteins. Immunohistochemical examination of pretherapeutic tumor biopsies for expression of apoptosis-regulating proteins may help to identify patients with LAEC who may benefit from multimodal treatment and those who may not.
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PMID:Expression of apoptosis-regulating proteins and outcome of esophageal cancer patients treated by combined therapy modalities. 986 11

Expression of several members of the Bcl-2 family proteins was investigated by means of both immunohistochemical analysis in 30 invasive ductal adenocarcinomas and 23 intraductal papillary-mucinous tumors (IPMTs) and immunoblot analysis in 6 cancer tissues and 7 pancreatic cancer cell lines. We found that Bcl-2 was expressed in 23%, Bax in 53%, Bcl-X in 90%, and Mcl-1 in 90% of the invasive ductal adenocarcinomas. In intraductal papillary-mucinous adenocarcinomas, the expression rate of Bax was 44% and those of Bcl-XL and Mcl-1 were 88%; these values were higher than those for intraductal papillary-mucinous adenomas. Immunoblot analysis identified Bcl-XL as the predominant form of the Bcl-X protein in both pancreatic cancer tissues and cell lines, and demonstrated that both Bcl-XL and Mcl-1 protein levels were uniformly high in all cell lines. These results suggest that an imbalance between antiapoptosis proteins (such as Bcl-2, Bcl-XL, and Mcl-1) and proapoptotic proteins (such as Bax and Bcl-Xs) is involved in the distinctive biologic features of adenocarcinomas of the pancreas. Furthermore, predominantly high expressions of Bcl-XL and Mcl-1 in intraductal papillary-mucinous adenocarcinomas might be involved in the carcinogenesis in IPMT of the pancreas.
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PMID:Immunohistochemical analysis of Bcl-2, Bax, Bcl-X, and Mcl-1 expression in pancreatic cancers. 988 81

We performed flow cytometric analysis of CD34+ cell apoptosis in 59 patients with myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) secondary to MDS (MDS-AML) using annexin V-FITC, which binds to exposed phosphatidylserine on apoptotic cells. Apoptosis was significantly increased in FAB subtypes RA, RARS and RAEB (<10% blasts) (56.5% (15.1-86.5%)) compared to normal controls (18.5% (3.4-33.4%), P<0.0001) and RAEB-t/MDS-AML (16% (2.1-43.2%), P<0.0001). There was no correlation between % apoptosis, Full blood count or cytogenetics in any disease category. Two-colour cytometric analysis of permeabilized CD34+ cells stained with antibodies to Bcl-2, Bcl-X (anti-apoptotic), Bax and Bad (pro-apoptotic), demonstrated significantly higher ratios of pro- v anti-apoptotic proteins in early MDS (2.47 (1.19-9.42) compared to advanced disease (1.14 (0.06-3.32), P=0.0001). Moreover, using repeated measures of variants (ANOVA), we found that variations between individual Bcl-2-related proteins differed significantly according to disease subtype (P<0.0005). Our results confirm that CD34+ cell apoptosis was significantly increased in MDS subtypes RA and RARS and fell with disease progression. Early MDS was also associated with a significantly higher CD34+ cell pro- v anti-apoptotic Bcl-2-family-protein ratio than advanced disease. Furthermore, patterns of expression of individual Bcl-2 related proteins differed significantly between different disease categories. However, no correlation between pro- v anti-apoptotic Bcl-2-family-protein ratios and the degree of apoptosis was observed.
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PMID:'Low-risk' myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of pro- versus anti-apoptotic bcl-2-related proteins. 988 23

The proteasome inhibitors lactacystin and AcLLNal induced p53-independent apoptosis in two human glioma cell lines, and the apoptosis was accompanied by up-regulation of immunoreactive wild-type p53, p21Waf1, Mdm2, and p27Kip1. Pretreatment with cycloheximide decreased the induction of cell death independently of p53 protein status, suggesting that the up-regulation of short-lived proteins is associated with proteasome inhibitor-induced apoptosis. Caspase-3-like proteases were activated in the proteasome inhibitor-mediated apoptosis, and the induction of cell death was inhibited more effectively in the presence of z-VAD.fmk than in the presence of Ac-DEVD.fmk, suggesting that caspases other than caspase-3 are involved. Nonetheless, there were no significant alterations in levels of immunoreactive Bcl-2, Bcl-X(L), Bax, Bad, and Bak, nor any evidence of cytochrome c release into cytosol and dissipation of delta(psi)m. Thus, the proteasome inhibitor-induced apoptosis is mediated by a mitochondria-independent mechanism, and the once activated caspase-3 does not cause the cytochrome c release and the delta(psi)m disruption.
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PMID:Proteasome inhibitors induce mitochondria-independent apoptosis in human glioma cells. 998 1

It has been suggested that the C-terminal domain of Bcl-2 family members may contain a signal anchor sequence that targets these proteins to the mitochondrial outer membrane. We have investigated the consequence of deleting this domain upon cytochrome c release in yeast strains that coexpress truncated forms of Bax (i.e. BaxA) and Bcl-X(L) (i.e. Bcl-X(L)delta). We find that (i) Bax(delta) is as efficient as full-length Bax in promoting cytochrome c release, but Bcl-x(L)delta has remarkably reduced rescuing ability compared to full-length Bcl-x(L); (ii) full-length Bcl-X(L) protein acts by relocalizing Bax from the mitochondrial fraction to the soluble cytosolic fraction; (iii) Bax undergoes N-terminal cleavage when expressed in yeast, which is prevented by coexpression of Bcl-X(L), suggesting that Bcl-x(L) may mask the cleavage site of Bax through a direct physical interaction of the two proteins.
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PMID:Role of the C-terminal domain of Bax and Bcl-XL in their localization and function in yeast cells. 998 10

The cyclin-dependent kinase inhibitor p27Kip1 has been implicated as a drug resistance factor in tumor cells grown as spheroids or confluent monolayers. Here, we show that p27Kip1 overexpression also induces resistance to drug-induced apoptosis and cytotoxicity in human leukemic cells growing in suspension. The anti-apoptotic effect of p27Kip1 is not restricted to DNA-damaging agents but extends to the tubulin poison vinblastin, agonistic anti-Fas antibodies and macromolecule synthesis inhibitors. To further identify at which level this protein interferes with the cell death pathway, we investigated its influence on caspase activation and mitochondrial changes. Exposure of mock-transfected U937 cells to 50 microm etoposide activates procaspase-3 and the long isoform of procaspase-2 and induces mitochondrial potential decrease and cytochrome c release from mitochondria to the cytosol. All these events are prevented by p27Kip1 overexpression. p27Kip1 does not modulate Bcl-2, Bcl-X(L), Mcl-1 and Bax protein level in leukemic cells but suppresses Mcl-1 expression decrease observed in mock-transfected U937 cells undergoing etoposide-induced cell death. We conclude that p27Kip1 prevents cell death upstream of the final pathway common to many apoptotic stimuli that involves cytochrome c release from mitochondria and activation of downstream caspases.
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PMID:p27Kip1 induces drug resistance by preventing apoptosis upstream of cytochrome c release and procaspase-3 activation in leukemic cells. 1005 Aug 78

Testicular germ cell tumours are hypersentive to chemotherapy and cell lines derived from these tumours are chemosensitive in vitro. We have previously shown that these cell lines express undetectable levels of the suppressor of apoptosis Bcl-2 and relatively high levels of the apoptosis inducer Bax (Chresta et al., 1996). To determine whether the absence of Bcl-2 in these cell lines makes them highly susceptible to drug-induced apoptosis, Bcl-2 was expressed ectopically in the 833K testicular germ cell tumour cell line. Stable overexpressing clones were isolated and three clones were studied further. Surprisingly, Bcl-2 overexpressing cells were sensitized to chemotherapy-induced apoptosis compared to the parental and vector control cells. Analysis of potential mechanisms of sensitization revealed there was a reciprocal downregulation of the endogenously expressed Bcl-X(L) in the Bcl-2 overexpressing clones. Downregulation of Bcl-X(L) to the same extent using antisense oligonucleotides enhanced etoposide-induced apoptosis by twofold. Our results indicate that Bcl-2 and Bcl-X(L) have different abilities to protect against chemotherapy-induced apoptosis in testicular germ cell tumours. In contrast to findings in some tumour cell types, Bcl-2 did not act as a gatekeeper to prevent entry of p53 to the nucleus.
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PMID:Bcl-2 overexpression results in reciprocal downregulation of Bcl-X(L) and sensitizes human testicular germ cell tumours to chemotherapy-induced apoptosis. 1005 Aug 82

Amplification of the MYCN gene is found in a large proportion of neuroblastoma and considered as an adverse prognostic factor. To investigate the effect of ectopic MycN expression on the susceptibility of neuroblastoma cells to cytotoxic drugs we used a human neuroblastoma cell line harboring tetracycline-controlled expression of MycN. Neither conditional expression of MycN alone nor low drug concentrations triggered apoptosis. However, when acting in concert, MycN and cytotoxic drugs efficiently induced cell death. Apoptosis depended on mitochondrial permeability transition and activation of caspases, since the mitochondrion-specific inhibitor bongkrekic acid and the caspase inhibitor zVAD-fmk almost completely abrogated apoptosis. Loss of mitochondrial transmembrane potential and release of cytochrome c from mitochondria preceded activation of caspase-8 and caspase-3 and cleavage of PARP. CD95 expression was upregulated by treatment with cytotoxic drugs, while MycN cooperated with cytotoxic drugs to increase sensitivity to CD95-induced apoptosis and enhancing CD95-L expression. MycN overexpression and cytotoxic drugs also synergized to induce p53 and Bax protein expression, while Bcl-2 and Bcl-X(L) protein levels remained unchanged. Since amplification of MYCN is usually associated with a poor prognosis, these findings suggest that dysfunctions in apoptosis pathways may be a mechanism by which MycN-induced apoptosis of neuroblastoma cells is inhibited.
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PMID:MycN sensitizes neuroblastoma cells for drug-induced apoptosis. 1005 Aug 84


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