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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis is a form of physiological cell death, characterized by chromatin condensation, cytoplasmic blebbing and DNA fragmentation, which often depends on RNA and protein synthesis by the dying cell. The c-myc proto-oncogene, usually implicated in cell transformation, differentiation and cell-cycle progression also has a central role in some forms of apoptosis. These opposing roles of myc in cell growth and death require that other gene products dictate the outcome of c-Myc expression on a cell. A candidate for such a modifying gene is bcl-2, whose product prolongs cell survival and blocks apoptosis in some systems. Here we demonstrate that Bcl-2 prevents apoptotic death induced by c-Myc, provide a mechanism whereby cells can express c-Myc without undergoing apoptosis, and give a possible explanation for the ability of Bcl-2 to synergize with c-Myc in cell transformation.
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PMID:Apoptotic cell death induced by c-myc is inhibited by bcl-2. 140 75

Correlations between cytogenetics, histology, and clinical course continue to emerge in studies of non-Hodgkin's lymphomas. The previously recognized association between the t(14;18) chromosomal translocation and follicular lymphoma has been confirmed; abnormalities of chromosome 3 have correlated specifically with diffuse large cell lymphoma and abnormalities of chromosome 1 have been frequently present in T-cell lymphomas. Rearrangements involving 11q13 (bcl-1) occur most commonly in diffuse lymphocytic lymphoma of intermediate differentiation. Several new recurrent chromosomal abnormalities have also been described. The molecular fine structure of the t(8-14) chromosomal translocation in Burkitt's lymphoma appears to differ between endemic (Epstein-Barr virus-associated) and sporadic cases. In endemic Burkitt's lymphomas, the chromosomal breakpoint is usually far upstream of c-myc oncogene, leaving the regulatory region of the gene intact. In sporadic tumors, a large part of the regulatory region is separated from the gene and transcription is initiated at sites within the first intron. These data raise the possibility that Epstein-Barr virus may contribute to the deregulation of the c-myc gene and that this interaction may be required for tumorigenesis in the presence of some, but not all, types of c-myc damage arising from chromosomal translocations. Partner proteins that oligomerize with c-Myc have been identified in humans and mice (Max and Myn). The partners share with c-Myc the DNA-binding and coiled-coil motifs that are recognized in many other proteins and that function as transcriptional regulators. The Bcl-2 protein has been shown to be a mitochondrial inner membrane protein that blocks programmed cell death (apoptosis). Viral expression has been demonstrated in Epstein-Barr virus-associated Hodgkin's disease, and the spectrum of Epstein-Barr virus-associated lymphoproliferative disease has been expanded to include some T-cell malignancies. A new human herpesvirus has been associated with some cases of Hodgkin's disease.
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PMID:Biology of the lymphomas: cytogenetics, molecular biology, and virology. 166 Nov 67

Mad is a bHLH/Zip protein that, as a heterodimer with Max, can repress Myc-induced transcriptional transactivation. Expression of Mad is induced upon terminal differentiation of several cell types, where it has been postulated to down-regulate Myc-induced genes that drive cell proliferation. Here we show that Mad also blocks transformation of primary rat embryo fibroblasts by c-Myc and the activated c-Ha-Ras oncoproteins. Mad mutants lacking either the basic region, the leucine zipper, or an intact NH2-terminal protein interaction domain fail to inhibit Myc-Ras cotransformation. These results indicate that the repression of cotransformation requires DNA-binding and is mediated by multiple protein-protein interactions involving both Max and mSin3, a putative mammalian corepressor protein. With increasing amounts of the cotransfected myc gene, the numbers of transformed foci are reduced and the ability of Mad to inhibit focus formation is attenuated. Moreover, cell lines derived from such foci constitutively express both Myc and Mad proteins. Whereas Bcl-2 can significantly increase the numbers of transformed foci by enhancing the survival of myc-ras-transfected cells, it does not counteract the repressive effects of Mad on transformation, suggesting that Mad affects the growth properties rather than the viability of cells. Taken together, our results demonstrate that Mad is capable of antagonizing the biological effects of Myc and thereby suggest that Mad could function as a tumor suppressor gene.
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PMID:Repression of Myc-Ras cotransformation by Mad is mediated by multiple protein-protein interactions. 766 17

There are independent signaling pathways which transmit apoptotic signals in thymocytes. c-Myc and p53 proteins participate in the apoptosis induction, whereas Bcl-2 and Pim-1 proteins inhibit complex apoptotic machinery.
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PMID:[Diversity of signal transduction pathways which induce apoptosis of thymocytes. Role of bcl-2, pim-1, c-myc and p53 genes in selection processes of thymocytes]. 767 28

The Two Signal: Death/Survival Model suggests that cellular proliferation and physiological cell death should be intimately associated such that, in the absence of external influences, a normal cell departing from rest will have an equal probability of undergoing either process. The c-Myc protooncogene product has been implicated in cell cycle progression and in the control of gene expression, and more recently c-Myc has also been seen to promote apoptotic cell death. As predicted from the model, c-Myc-induced apoptosis is inhibited by growth factors or other anti-apoptotic signals including those provided by some oncogenes. Here, we discuss experiments that test the Two Signal: Death/Survival Model in the phenomenon of activation-induced apoptosis in T-cell hybridomas. Ligation of the antigen receptor on these cells leads to activation, resulting in cytokine production and apoptosis. Inhibition of c-Myc expression by addition of antisense oligodeoxynucleotides or transforming growth factor beta inhibits this form of apoptosis. Because c-Myc is known to bind to several cellular proteins, including Max, we further examined the effects of expression of a dominant negative Max on activation-induced apoptosis. We found that this Max mutant, which interferes with the function of the Myc/Max heterodimer, inhibits the induction of apoptosis by antigen receptor ligation. Thus, both Myc and Max play roles in activation-induced apoptosis, presumably via control of gene expression. Further, as predicted, signals generated from growth factor receptors or the v-Abl oncogene interfere with activation-induced apoptosis. In contrast, the anti-apoptotic effects of Bcl-2 are not active in this form of apoptosis. Finally, a role for Fas/Fas-ligand interactions in activation-induced apoptosis is considered.
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PMID:Promotion and inhibition of activation-induced apoptosis in T-cell hybridomas by oncogenes and related signals. 769 99

The expression of retinoblastoma (Rb), c-Myc and Bcl-2 proteins was studied by immunohistochemical methods in 104 cases of renal adenocarcinoma. One tumour was completely negative for Rb protein and altered expression pattern was detected in 36% of cases. A low fraction of Rb-positive nuclei was related to high grade (P = 0.016) and high mitotic index (P = 0.012). Twenty-eight per cent of the tumours expressed c-Myc in cancer cell nuclei and 87% showed cytoplasmic positivity. Cytoplasmic expression of c-Myc was related to high grade (P = 0.002), while nuclear expression of c-Myc was related to small tumour diameter (P = 0.034), low T category (P = 0.04), low mitotic index (P = 0.019) and expression of c-ErbB-2 (P = 0.0007). Overexpression of c-myc predicted favourable outcome in M0 tumours (P = 0.0157). Bcl-2 was expressed in 20% of tumours and it was related to small tumour size (P < 0.0001), low T category (P < 0.0001), lack of venous invasion (P = 0.008), node negativity (P = 0.015) and absence of metastasis (P = 0.017). In multivariate analysis the expression of Rb, Bcl-2 and c-Myc had no independent prognostic value over T category (P < 0.001), mitotic index (P = 0.008) and combined nuclear grade (P = 0.056).
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PMID:Expression of tumour-suppressor gene Rb, apoptosis-suppressing protein Bcl-2 and c-Myc have no independent prognostic value in renal adenocarcinoma. 771 Sep 55

Two interleukin-2 receptor-dependent signaling pathways have thus far been identified: the c-fos/c-jun induction pathway mediated by src family protein-tyrosine kinases and the c-myc induction pathway. Here, we provide evidence for the existence of a third, rapamycin-sensitive pathway, which results in the induction of another proto-oncogene, bcl-2. In the hematopoietic cell line BAF-B03, the expression of any two of lckF505 (an active form of p56lck), Bcl-2, or c-Myc is sufficient to promote transit of the cell cycle, regardless of the activation state of the third pathway. We also provide evidence that epidermal growth factor receptor signaling may act through the same pathway that involves p56lck. These studies demonstrate a novel approach to dissecting signaling pathways regulating cellular proliferation.
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PMID:Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation. 773 74

When deprived of autocrine growth factors, Epstein-Barr virus (EBV)-immortalized B cells stop growing and die. In this study, we show that death of EBV-immortalized cells deprived of autocrine growth factors occurred by apoptosis. Cycloheximide, a protein synthesis inhibitor, inhibited apoptosis, suggesting that de novo protein synthesis is required. Because p53, Bcl-2, and c-Myc were previously implicated in the induction or prevention of apoptosis in other systems, we assessed their possible involvement here. Unlike normal cells that respond to growth factor deprivation by down-regulating c-Myc expression, EBV-immortalized cells continued to express c-Myc, p53, and Bcl-2 at levels comparable to those measured prior to starvation. Consistent with data demonstrating that c-Myc expression is sufficient to drive quiescent cells into the cell cycle, autocrine growth factor-deprived EBV-immortalized cells did not undergo growth arrest but rather continued to proliferate until death, which occurred randomly throughout the cell cycle. In contrast to EBV-immortalized B cells, normal peripheral blood B cells activated in vitro with anti-CD40 monoclonal antibody and interleukin 4 rapidly down-regulated c-Myc expression and underwent growth arrest in response to growth factors and serum deprivation. These findings demonstrated that c-Myc expression is deregulated in EBV-immortalized cells. Addition of antisense oligonucleotides to c-Myc specifically promoted the survival of starved EBV-immortalized cells and suppressed growth of nonstarved EBV-immortalized cells. Thus, deregulated expression of c-Myc in EBV-immortalized cells promotes proliferation and apoptosis following autocrine growth factor deprivation.
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PMID:A role for deregulated c-Myc expression in apoptosis of Epstein-Barr virus-immortalized B cells. 780 56

The v-Rel oncoprotein of the avian Rev-T retrovirus malignantly transforms chicken spleen cells in vivo and in vitro. We previously described two temperature-sensitive (ts) mutants of v-Rel (v-G37E and v-R273H) that show a ts ability to transform chicken spleen cells and to bind to DNA in vitro. We now show that spleen cell lines transformed by ts v-Rel proteins at the permissive temperature undergo apoptosis when cells are shifted to the nonpermissive temperature. The levels of most proteins (including v-Rel, p53, c-Myc, Rb and Bcl-2) do not change in these cells even at advanced stages of apoptosis. However, the chicken I kappa B-alpha protein (also called p40), which is in a complex with v-Rel in transformed cells, is degraded when ts v-Rel-transformed cells are shifted to the nonpermissive temperature. In v-R273H-transformed cells, p40 is degraded without the appearance of proteolytic intermediates. In contrast, in v-G37E-transformed cells, p40 is cleaved to an intermediate species that is missing approximately 3-4 kDa from its amino terminus. This truncated form of p40 is found in a detergent-insoluble fraction and can also be detected in wild-type v-Rel-transformed cells that are induced to undergo apoptosis by treatment with cycloheximide. Both ts v-Rel proteins are ts for interaction with p40 in vitro. The results reported here indicate that v-Rel blocks a normal pathway of programmed cell death and that I kappa B-alpha can undergo multiple degradative pathways, which can be induced by alterations in the structure of the Rel protein to which it is bound.
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PMID:The v-Rel oncoprotein blocks apoptosis and proteolysis of I kappa B-alpha in transformed chicken spleen cells. 789 28

Derivatives of the murine bone marrow-derived, IL-3-dependent cell line, BAF3, were isolated following recombinant retroviral infection which showed disregulated expression of human c-Myc oncoprotein. Such cells entered apoptosis and lost viability more rapidly than parental BAF3 cells when IL-3 was removed. c-Myc disregulation also resulted in an inability of BAF3 cells to survive in either sub-optimal concentrations of IL-3, or saturating concentrations of IL-4 and insulin-like growth factor-1. Furthermore, BAF3 cells with disregulated c-Myc expression were more sensitive to the induction of apoptosis by DNA-damaging agents. These effects of c-Myc disregulation could be inhibited by co-expression of the Bcl-2 oncoprotein. The implications of these data for the transformation of haematopoietic cells by disregulation of Myc expression are discussed.
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PMID:Disregulation of Myc expression in murine bone marrow cells results in an inability to proliferate in sub-optimal growth factor and an increased sensitivity to DNA damage. 798 Nov 46


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