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)

The Bcl-2 family of proteins play a prominent role in the regulation of apoptosis. From the initial identification of bcl-2 as an oncogene in follicular lymphoma through genetic studies in Caenorhabditis elegans to recent functional studies focusing on the importance of mitochondrial events in cell death signalling, the members of this protein family continue to be implicated in pivotal decision points regarding the survival of the cell. The family can be divided into two classes: those such as Bcl-2 and Bcl-xL that suppress cell death, and others, such as Bak and Bax, that appear to promote apoptosis. The Bcl-2 family is characterized by specific regions of homology termed Bcl-2 homology (BH1, BH2, BH3, BH4) domains, which are critical to the function of these proteins, including their impact on cell survival and their ability to interact with other family members and regulatory proteins. The identification of the BH3 domain as a potent mediator of cell death has led to the emergence of an additional family of proapoptotic proteins (such as Bad, Bik, Bid and Hrk) that share identity with Bcl-2 only within this death domain. These BH3-only proteins may be part of a regulatory network serving to integrate cell survival and death signals, an assertion that is supported by the identification of a BH3-only protein, Egl-1, as part of the central core of cell death signalling in C. elegans. While the mechanism of action of the BH3-only proteins remains unclear, recent studies on the regulation of critical protein-protein interactions and activity of Bad by phosphorylation in response to growth factor signalling suggest that the active state of BH3-only proteins may be regulated by post-translational modification. Additional modes of regulation, such as transcriptional, translational and subcellular localization, are also likely to be important.
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PMID:Role of the BH3 (Bcl-2 homology 3) domain in the regulation of apoptosis and Bcl-2-related proteins. 1081 98

The mechanism underlying apoptosis induced by proteasome inhibition in leukemic Jurkat and Namalwa cells was investigated in this study. The proteasome inhibitor lactacystin differentially regulated the protein levels of proapoptotic Bcl-2 family members and Bik was accumulated at the mitochondria. Bik overexpression sufficed to induce apoptosis in these cells. Detailed examination along the respiration chain showed that lactacystin compromised a step after complex III, and exogenous cytochrome c could overcome this compromise. Probably as a result, the succinate-stimulated generation of mitochondrial membrane potential was significantly diminished. Bcl-x(L) interacted with Bik in the cells, and Bcl-x(L) overexpression prevented cytochrome c leakage out of the mitochondria, corrected the mitochondrial membrane potential defect, and protected the cells from apoptosis. These results show that proteasomes can modulate apoptosis of lymphocytes by affecting the half-life of Bcl-2 family members, Bik being one of them.
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PMID:Proteasomes modulate balance among proapoptotic and antiapoptotic Bcl-2 family members and compromise functioning of the electron transport chain in leukemic cells. 1120 65

The Bcl-2 family of proteins plays a central regulatory role in apoptosis. We have identified a novel, widely expressed Bcl-2 member which we have named Bcl-rambo. Bcl-rambo shows overall structural homology to the anti-apoptotic Bcl-2 members containing conserved Bcl-2 homology (BH) motifs 1, 2, 3, and 4. Unlike Bcl-2, however, the C-terminal membrane anchor region is preceded by a unique 250 amino acid insertion containing two tandem repeats. No interaction of Bcl-rambo with either anti-apoptotic (Bcl-2, Bcl-x(L), Bcl-w, A1, MCL-1, E1B-19K, and BHRF1) or pro-apoptotic (Bax, Bak, Bik, Bid, Bim, and Bad) members of the Bcl-2 family was observed. In mammalian cells, Bcl-rambo was localized to mitochondria, and its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs, whereas inhibitors controlling upstream events of either the 'death receptor' (FLIP, FADD-DN) or the 'mitochondrial' pro-apoptotic pathway (Bcl-x(L)) had no effect. Surprisingly, the Bcl-rambo cell death activity was induced by its membrane-anchored C-terminal domain and not by the Bcl-2 homology region. Thus, Bcl-rambo constitutes a novel type of pro-apoptotic Bcl-2 member that triggers cell death independently of its BH motifs.
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PMID:Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension. 1126 95

Through direct interaction with the voltage-dependent anion channel (VDAC), proapoptotic members of the Bcl-2 family such as Bax and Bak induce apoptogenic cytochrome c release in isolated mitochondria, whereas BH3-only proteins such as Bid and Bik do not directly target the VDAC to induce cytochrome c release. To investigate the biological significance of the VDAC for apoptosis in mammalian cells, we produced two kinds of anti-VDAC antibodies that inhibited VDAC activity. In isolated mitochondria, these antibodies prevented Bax-induced cytochrome c release and loss of the mitochondrial membrane potential (Deltapsi), but not Bid-induced cytochrome c release. When microinjected into cells, these anti-VDAC antibodies, but not control antibodies, also prevented Bax-induced cytochrome c release and apoptosis, whereas the antibodies did not prevent Bid-induced apoptosis, indicating that the VDAC is essential for Bax-induced, but not Bid-induced, apoptogenic mitochondrial changes and apoptotic cell death. In addition, microinjection of these anti-VDAC antibodies significantly inhibited etoposide-, paclitaxel-, and staurosporine-induced apoptosis. Furthermore, we used these antibodies to show that Bax- and Bak-induced lysis of red blood cells was also mediated by the VDAC on plasma membrane. Taken together, our data provide evidence that the VDAC plays an essential role in apoptogenic cytochrome c release and apoptosis in mammalian cells.
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PMID:Essential role of voltage-dependent anion channel in various forms of apoptosis in mammalian cells. 1126 42

In recent years chimeric proteins carrying bacterial toxins as their killing moiety, have been developed to selectively recognize and kill cell populations expressing speciific receptors. The involvement of Gonadotropin releasing hormone (GnRH) has been demonstrated in several adenocarcinomas and a GnRH-bacterial toxin chimeric protein (GnRH-PE66) was thus developed and found to specifically target and kill adenocarcinoma cells both in vitro and in vivo. Because of the immunogenicity and the non-specific toxicity of the bacterial toxins, we have developed new chimeric proteins, introducing apoptosis inducing proteins of the Bcl-2 family as novel killing components. Sequences encoding the human Bik, Bak or Bax proteins were fused to the GnRH coding sequence at the DNA level and were expressed in E. coli. GnRH-Bik, GnRH-Bak and GnRH-Bax new chimeric proteins efficiently and specifically inhibited the cell growth of adenocarcinoma cell lines and eventually led to cell death. All three Bcl2-proteins-based chimeric proteins seem to induce apoptosis within the target cells, without any additional cell death stimulus. Apoptosis-inducing-proteins of the Bcl-2 family targeted by the GnRH are novel potential therapeutic reagents for adenocarcinoma treatment in humans. This novel approach could be widely applied, using any molecule that binds a specific cell type, fused to an apoptosis-inducing protein.
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PMID:GnRH-Bik/Bax/Bak chimeric proteins target and kill adenocarcinoma cells; the general use of pro-apoptotic proteins of the Bcl-2 family as novel killing components of targeting chimeric proteins. 1130 12

One of the main functions of the tumor suppressor p53 is the induction of programmed cell death. Here we investigated in detail the molecular mechanisms that underlay p53 transactivation-dependent apoptosis in the human colon cancer cell line DLD-1. Although p53 upregulated the death receptors Fas, TRAIL-R1 and TRAIL-R2 in this cell line, p53-induced cell death occurred without detectable caspase-8 activation whereas, activation of caspase-9 and caspase-3 was readily observed. In addition to the upregulation of death receptors, p53 induced the pro-apoptotic Bcl-2 family members Bik and Bak and downregulated the anti-apoptotic Bcl-xL protein. Moreover, in RNase protection assay analyses as well as in reporter gene analyses we found a p53-dependent upregulation of the death receptor-inhibitory protein cFLIP. Together, these data argue for a p53-mediated activation of the mitochondrial pathway of apoptosis. In contrast to recently published data obtained in different cellular systems, there was no evidence for an essential role of NF-kappaB in p53-induced cell death. Moreover, induction of p53 interfered with TNF-induced NF-kappaB activation independently from apoptosis-induction.
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PMID:p53 upregulates cFLIP, inhibits transcription of NF-kappaB-regulated genes and induces caspase-8-independent cell death in DLD-1 cells. 1131 89

Apoptosis plays a central role in shaping the repertoire of circulating mature B lymphocytes, but the underlying molecular mechanisms regulating B cell fate are not well understood. Human B104 B lymphoma cells undergo apoptosis after surface Ig (sIg)M, but not sIgD, ligation; sIgM-mediated apoptosis of B104 cells apparently requires new gene transcription because actinomycin D can inhibit the apoptotic response. Here we report that expression of Bik, a proapoptotic member of the Bcl-2 family, is greatly increased after sIgM ligation. Bik expression was tightly controlled at both transcriptional and post-transcriptional levels. Whereas a calcineurin-dependent pathway was essential for Bik mRNA induction, both the phosphatidylinositol 3-kinase (PI3K)- and the calcineurin-dependent pathways were required for the sustained production of Bik protein. Consistent with these findings, sIgD ligation, which leads to the similar calcium mobilization and increases in Bik mRNA, induced only a transient activation of PI3K and did not lead to sustained Bik protein expression. Furthermore, sustained Bik protein expression correlated with B cell apoptosis, as treatment with either a calcineurin inhibitor or PI3K inhibitors blocked both sIgM-mediated sustained Bik protein induction and apoptosis. In addition, sIgM ligation strongly increased the amount of Bik associated with endogenous Bcl-x, but sIgD ligation did not. Studies with caspase inhibitors also revealed that Bik and Bcl-x interacted upstream of caspases in the B cell apoptosis cascade. Thus, Bik protein induction and, subsequently, sequestering of antiapoptotic Bcl-x by Bik may play an important role in regulating B cell apoptosis.
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PMID:Involvement of Bik, a proapoptotic member of the Bcl-2 family, in surface IgM-mediated B cell apoptosis. 1134 19

Type 2 diabetes is characterized by insulin resistance and inadequate insulin secretion. In the advanced stages of the disease, beta-cell dysfunction worsens and insulin therapy may be necessary to achieve satisfactory metabolic control. Studies in autopsies found decreased beta-cell mass in pancreas of people with type 2 diabetes. Apoptosis, a constitutive program of cell death modulated by the Bcl family genes, has been implicated in loss of beta-cells in animal models of type 2 diabetes. In this study, we compared the effect of 5 days' culture in high glucose concentration (16.7 mmol/l) versus normal glucose levels (5.5 mmol/l) or hyperosmolar control (mannitol 11 mmol/l plus glucose 5 mmol/l) on the survival of human pancreatic islets. Apoptosis, analyzed by flow cytometry and electron and immunofluorescence microscopy, was increased in islets cultured in high glucose (HG5) as compared with normal glucose (NG5) or hyperosmolar control (NG5+MAN5). We also analyzed by reverse transcriptase-polymerase chain reaction and Western blotting the expression of the Bcl family genes in human islets cultured in normal glucose or high glucose. The antiapoptotic gene Bcl-2 was unaffected by glucose change, whereas Bcl-xl was reduced upon treatment with HG5. On the other hand, proapoptotic genes Bad, Bid, and Bik were overexpressed in the islets maintained in HG5. To define the pancreatic localization of Bcl proteins, we performed confocal immunofluorescence analysis on human pancreas. Bad and Bid were specifically expressed in beta-cells, and Bid was also expressed, although at low levels, in the exocrine pancreas. Bik and Bcl-xl were expressed in other endocrine islet cells as well as in the exocrine pancreas. These data suggest that in human islets, high glucose may modulate the balance of proapoptotic and antiapoptotic Bcl proteins toward apoptosis, thus favoring beta-cell death.
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PMID:High glucose causes apoptosis in cultured human pancreatic islets of Langerhans: a potential role for regulation of specific Bcl family genes toward an apoptotic cell death program. 1137 29

The human neutrophil spontaneously undergoes apoptosis, but this type of cell death can be delayed or accelerated by a wide variety of agents. There are wide discrepancies in the literature regarding the expression of the Bcl-2 family of proteins in human neutrophils. Here, we show that A1, Mcl-1, Bcl-X(L), and Bad are major transcripts in human neutrophils and that levels of these transcripts are cytokine regulated. However, no Bcl-X(L) protein was detected in Western blots. Protein levels for the proapoptotic proteins Bad, Bax, Bak, and Bik remained constant during culture, despite changes in the levels of mRNA for these gene products. These proapoptotic proteins were extremely stable, having very long half-lives. In contrast, A1 and Mcl-1 transcripts were extremely unstable (with approximately 3-h half-lives), and Mcl-1 protein was also subject to rapid turnover. These results indicate that neutrophil survival is regulated by the inducible expression of the short-lived Mcl-1 and possibly the A1 gene products. In the absence of their continued expression, these prosurvival gene products are rapidly turned over, and then the activity of the stable death proteins predominates and promotes apoptosis.
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PMID:BCL-2 family expression in human neutrophils during delayed and accelerated apoptosis. 1169 99

We previously demonstrated that the forced expression of pro-caspase-3 can revert acquired chemoresistance in MT1-Adr breast cancer cells which show a defective activation of the mitochondrial pathway of apoptosis. We now asked whether the manipulation of mitochondrial apoptosis signaling can revert different types of drug resistance, i.e. the resistance due to impaired mitochondrial activation in the MT1-Adr cells and the resistance in MT3-Adr cells which is caused by increased expression of the Mdr-1/p-glycoprotein ABC transporter. Here we show that Bcl-2 overexpression is the underlying cause for the resistant phenotype in the MT1-Adr cells. Overexpression of the apoptosis-promoting Bax homologue Bak or the BH3 only protein Nbk/Bik reverts, as expected, acquired drug resistance in the MT1-Adr cells as recently demonstrated for pro-caspase-3. Moreover, we show that both apoptosis-promoters, Nbk/Bik and Bak, antagonize acquired chemoresistance for epirubicin-mediated apoptosis in MT3-Adr breast cancer cells. Neither drug uptake nor drug efflux were influenced by Bak or Nbk/Bik. Thus, our data show that manipulation of the downstream apoptosis signaling cascade by Bak and Nbk/Bik can overcome not only drug resistance due to mitochondrial apoptosis deficiency (in the MT1-Adr cells) but also classical, i.e. efflux-mediated, resistance for drug-induced cell death in the MT3-Adr cell line. Nbk/Bik and Bak could therefore be target genes to increase chemosensitivity and overcome different types of drug resistance.
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PMID:The apoptosis promoting Bcl-2 homologues Bak and Nbk/Bik overcome drug resistance in Mdr-1-negative and Mdr-1-overexpressing breast cancer cell lines. 1180 66


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