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

Bcl-2 gene product functions to prevent apoptosis in a variety of in vitro and in vivo experiments. The prognostic significance of Bcl-2 protein expression was investigated by immunocytochemistry from paraffin-embedded tissue in a series of 174 women with breast cancer, treated with radical surgery with or without regional radiotherapy, and who had been followed up for the median of 31 years or until death. A minority (25%) of cancers were entirely negative for Bcl-2 protein. Moderate to strong Bcl-2 protein expression (present in 46%) was strongly associated with several favorable prognostic features, such as a low mitotic count, high histological grade of differentiation, and lack of p53 protein expression (P < 0.0001 for each). It was also significantly associated with lack of tumor necrosis, a low S-phase fraction size, low cathepsin D expression, DNA diploidy, and the lobular histological type, but not with the primary tumor size or the axillary nodal status. Women with cancer with moderate to strong Bcl-2 protein expression had more favorable short-term (69% versus 46% alive at 5 years) but similar long-term (29% versus 33% alive at 30 years) disease-specific survival as those with cancer with weak or lacking expression. Bcl-2 protein expression did not have independent prognostic value in a multivariate survival analysis. We conclude that Bcl-2 protein is frequently expressed in breast cancer, and its expression is associated with favorable clinicopathological features.
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PMID:Bcl-2 protein expression and long-term survival in breast cancer. 797 49

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

Mcl-1, a protein increased early in the differentiation of human myeloblastic ML-1 cells, has sequence similarity to Bcl-2. In the present study, we determined whether Mcl-1 has functional similarity to Bcl-2 by testing its ability to inhibit apoptosis induced by c-Myc overexpression. This was carried out using Chinese hamster ovary 5AHSmyc cells which contain the human c-myc proto-oncogene under the control of a heat shock promoter. Heat treatment induces c-Myc overexpression and thus apoptosis as determined by internucleosomal DNA fragmentation. We transfected 5AHSmyc cells with mcl-1 and found that clones expressing the introduced Mcl-1 protein exhibited reduced DNA fragmentation. Mcl-1 was also capable of delaying the onset of cell death as judged by loss of membrane integrity, although it could not provide complete protection from c-Myc overexpression. Thus, Mcl-1 has functional homology to Bcl-2 in that Mcl-1 can enhance cell viability under conditions that otherwise cause apoptosis.
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PMID:Mcl-1, a member of the Bcl-2 family, delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells. 798 27

Many non-Hodgkins B-cell lymphomas possess a deregulated bcl-2 gene resulting in a phenotype that is apparently resistant to programmed cell death (apoptosis). We have used a mouse lymphoma cell line (S49.1) that undergoes apoptosis in response to a variety of stimuli to determine the effect of bcl-2 expression on induction of apoptosis. S49 cells were stably transfected with recombinant amphotrophic retroviruses carrying either a G418 antibiotic resistance gene alone (S49-NEO) or this gene in combination with a bcl-2 complementary DNA (S49-Bcl-2). Three different agents previously shown to activate apoptosis by different pathways in S49 cells (dexamethasone, the calcium ionophore A23187, and cycloheximide) were used to examine the effect of bcl-2 expression on cell growth and apoptosis caused by multiple signal transduction pathways. Dexamethasone (DEX) treatment inhibited cell growth and stimulated cell death in S49-NEO cells. Although S49-Bcl-2 cells exhibited a similar antiproliferative response, they failed to die in response to steroid treatment. Western blot analysis revealed no difference in the levels of glucocorticoid receptor protein in the two cell lines, and both responded to glucocorticoid with a profound inhibition of protein synthesis. Cycloheximide (CX) and A23187 also had antiproliferative and cell killing effects in both cell types, although higher concentrations of each agent were needed to kill S49-Bcl-2 cells. To determine whether the loss of viability in response to these drugs was due to apoptosis, cells were examined morphologically and DNA integrity was examined by gel electrophoresis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bcl-2 inhibits glucocorticoid-induced apoptosis but only partially blocks calcium ionophore or cycloheximide-regulated apoptosis in S49 cells. 800 91

A complementary DNA for human bcl-2 was cloned into the replication competent avian retrovirus vector RCASBP, and the resulting virus was used to express human Bcl-2 protein at high levels in chicken embryo fibroblasts. The expression of Bcl-2 did not transform or significantly alter the longevity of the chicken embryo fibroblasts in the presence of normal amounts of serum. However, the expression of Bcl-2 blocked c-Myc-induced apoptosis in these cells. Fractionation of the infected chicken embryo fibroblasts indicated that the protein was distributed equally between nuclear and high density cytoplasmic membranes. Immunofluorescence analysis by confocal microscopy and immunoelectron microscopy showed that the Bcl-2 protein was primarily associated with the nuclear membrane and with the endoplasmic reticulum. Reduced amounts of the protein were associated with other membranes in the cytoplasm. These data show that, in this system, the Bcl-2 protein associates with the nuclear membrane and intracytoplasmic membranes but is not preferentially associated with mitochondria.
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PMID:Bcl-2 expressed using a retroviral vector is localized primarily in the nuclear membrane and the endoplasmic reticulum of chicken embryo fibroblasts. 804 16

The bcl-2 gene becomes dysregulated in its expression in a wide variety of human cancers and has been shown to block both spontaneous and drug-induced cell death, thus conferring a selective survival advantage on malignant cells. The biochemical mechanism by which bcl-2 promotes cell survival remains enigmatic but appears to involve a downstream event in an evolutionarily conserved cell death pathway. Here we report that gene transfer-mediated increases in Bcl-2 protein levels in the human leukemia line Jurkat render these cells more resistant to induction of DNA fragmentation and cytolysis by a cloned T-cell. The killing mechanism used by these particular T-cells was consistent with apoptosis, as opposed to necrosis, in that DNA degradation occurred as a prelysis event. The findings raise the possibility that dysregulation of bcl-2 gene expression could play a role in the avoidance of immune surveillance mechanisms by cancer cells.
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PMID:Bcl-2 inhibits T-cell-mediated cytolysis of a leukemia cell line. 806 51

Expression of the adenovirus E1A oncogene induces apoptosis which impedes both the transformation of primary rodent cells and productive adenovirus infection of human cells. Coexpression of E1A with the E1B 19,000-molecular-weight protein (19K protein) or the Bcl-2 protein, both of which have antiapoptotic activity, is necessary for efficient transformation. Induction of apoptosis by E1A in rodent cells is mediated by the p53 tumor suppressor gene, and both the E1B 19K protein and the Bcl-2 protein can overcome this p53-dependent apoptosis. The functional similarity between Bcl-2 and the E1B 19K protein suggested that they may act by similar mechanisms and that Bcl-2 may complement the requirement for E1B 19K expression during productive infection. Infection of human HeLa cells with E1B 19K loss-of-function mutant adenovirus produces apoptosis characterized by enhanced cytopathic effects (cyt phenotype) and degradation of host cell chromosomal DNA and viral DNA (deg phenotype). Failure to inhibit apoptosis results in premature host cell death, which impairs virus yield. HeLa cells express extremely low levels of p53 because of expression of human papillomavirus E6 protein. Levels of p53 were substantially increased by E1A expression during adenovirus infection. Therefore, E1A may induce apoptosis by overriding the E6-induced degradation of p53 and promoting p53 accumulation. Stable Bcl-2 overexpression in HeLa cells infected with the E1B 19K- mutant adenovirus blocked the induction of the cyt and deg phenotypes. Expression of Bcl-2 in HeLa cells also conferred resistance to apoptosis mediated by tumor necrosis factor alpha and Fas antigen, which is also an established function of the E1B 19K protein. A comparison of the amino acid sequences of Bcl-2 family members and that of the E1B 19K protein indicated that there was limited amino acid sequence homology between the central conserved domains of E1B 19K and Bcl-2. This domain of the E1B 19K protein is important in transformation and regulation of apoptosis, as determined by mutational analysis. The limited sequence homology and functional equivalency provided further evidence that the Bcl-2 and E1B 19K proteins may possess related mechanisms of action and that the E1B 19K protein may be the adenovirus equivalent of the cellular Bcl-2 protein.
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PMID:Functional complementation of the adenovirus E1B 19-kilodalton protein with Bcl-2 in the inhibition of apoptosis in infected cells. 808 92

The p53 tumor suppressor gene product is a transcriptional regulatory protein. It activates transcription from promoters that contain a p53 DNA binding site but represses many promoters that lack its binding site. High-level expression of wild-type p53 can induce apoptosis in certain cell types, and this activity can be blocked by the adenovirus E1B 19-kDa oncoprotein or by the cellular Bcl-2 oncoprotein. Here we report that p53-mediated repression of promoters that lack a p53 binding site is abrogated by the E1B 19-kDa protein or Bcl-2 oncoprotein. In contrast, transcriptional activation by p53 still occurs in the presence of either protein. The fact that two oncoproteins capable of preventing p53-mediated apoptosis also block transcriptional repression by p53 raises the possibility that p53 might induce apoptosis, at least in part, by repressing transcription.
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PMID:Relief of p53-mediated transcriptional repression by the adenovirus E1B 19-kDa protein or the cellular Bcl-2 protein. 809 Jul 49

The bcl-2 gene becomes transcriptionally deregulated in the majority of low-grade non-Hodgkin lymphomas as a result of t(14;18) translocations that place the bcl-2 gene at 18q21 into juxtaposition with the Ig heavy-chain locus at 14q32. This chromosomal translocation or similar bcl-2 gene rearrangements involving the Ig light-chain genes have been reported to occur in some cases of B-cell chronic lymphocytic leukemia (B-CLL). We analyzed the structure, methylation, and expression of the bcl-2 gene in 20 cases of B-CLL or closely related variants of this lymphoproliferative disorder, including at least 16 typical examples of CD5+ B-CLL. None of the 20 specimens had evidence of bcl-2 gene rearrangements, based on Southern blot analysis using three different bcl-2 probes. However, immunoblot analysis using antibodies specific for the Bcl-2 protein showed that 14 of 20 cases (70%) contained levels of p26-Bcl-2 that were equal to or greater than those found in a t(14;18)-bearing lymphoma cell line. Furthermore, in 19 of 20 cases (95%), the Bcl-2 protein was present at levels that were 1.7- to 25-fold higher than in normal peripheral blood lymphocytes. These differences in the relative levels of Bcl-2 protein among cases of B-CLL appeared to be functionally significant, in that a preliminary analysis of 3 representative cases showed that CLL cells with higher levels of Bcl-2 protein survived longer in culture and were delayed in their onset of DNA degradation relative to CLL cells with lower Bcl-2 protein levels. Evaluation of the methylation status of the bcl-2 gene using the isoschizomers Msp I and Hpa II, and a probe corresponding to the first major exon of the gene showed complete demethylation of both copies of the bcl-2 gene in a region corresponding to a 2.4-kb Msp I fragment in all 20 cases of B-CLL. In contrast, analysis of 6 of 6 B-cell lines that harbor a t(14;18) was consistent with hypomethylation of only one of the two bcl-2 alleles. Neither copy of the bcl-2 gene was demethylated in this region in 5 of 5 lymphoid cell lines that lack this translocation. However, hypomethylation of the bcl-2 gene did not necessarily correlate with the relative levels of Bcl-2 protein present in the B-CLL cells, suggesting that additional mechanisms for regulating bcl-2 expression are involved.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. 810 32

We reviewed recent reports on apoptosis and summarized the presentations at the Shirafu Cancer Symposium, 1993. The study of programmed cell death, apoptosis, has become one of the mainstream in cell biology, particularly in immunology, developmental biology and oncology. To determine whether the apoptotic cell death induced by anti-cancer agents could be inhibited by bcl-2, we established a bcl-2-transfected human small cell lung cancer cell line, SBC-3/Bcl-2. SBC-3/Bcl-2 showed higher resistance to ADM, CPT-11 and MMC compared with the parental line SBC-3. Agarose gel electrophoresis showed typical DNA fragmentation of SBC-3 following treatment with CPT-11 or MMC. In contrast, the same concentration of the drugs did not induce DNA fragmentation in SBC-3/Bcl-2. However, there was no difference in sensitivity to CDDP, VP-16, ACNU, MTX and Taxol between SBC-3 and SBC-3/Bcl-2 (Ohmori, T. et al. Biochem. Biophys. Res. Commun. 1993). These studies indicate that bcl-2 can modulate the cytotoxicity of some anti-cancer agents by inhibiting the process of apoptosis. We speculate that some apoptotic pathways are bcl-2-sensitive and others bcl-2-independent.
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PMID:[Anticancer agents and apoptosis]. 810 88


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