UNIPROT:P10415 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

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

The patterns of expression of the bcl-2, bax, and bci-X genes were examined immunohistochemically in neurons of the adult rat brain before and after 10 min of global ischemia induced by transient cardiac arrest. High levels of the cell death promoting protein Bax and concomitant low levels of the apoptosis-blocking protein Bcl-2 were found in some populations of neurons that are particularly sensitive to cell death induced by transient global ischemia, such as the CA1 sector of the hippocampus and the Purkinje cells of the cerebellum. Moreover, within 0.5 to 3 hr after an ischemic episode, immunostaining for Bax was markedly increased within neurons with morphological features of degeneration in many regions of the brain. Use of a two-color staining method for simultaneous analysis of Bax protein and in situ detection of DNA-strand breaks revealed high levels of Bax immunoreactivity in many neurons undergoing apoptosis. Postischemic elevations in Bax protein levels in the hippocampus, cortex, and cerebellum were also demonstrated by immunoblotting. At early times after transient ischemia, regulation of Bcl-2 and Bcl-x protein levels varied among neuronal subpopulations, but from 3 hr on, those neurons with morphological evidence of degeneration uniformly contained reduced levels of Bci-2 and particularly Bci-X immunoreactivity. The findings suggest that differential expression of some members of the bcl-2 gene family may play an important role in determining the relative sensitivity of neuronal subpopulations to ischemia and that postischemic alterations in the expression of bax, bcl-2, and bcl-x may contribute to the delayed neuronal cell death that occurs during the repurfusion phase after a transient ischemic episode.
...
PMID:Upregulation of bax protein levels in neurons following cerebral ischemia. 747 1

Bcl-2 and Bax are homologous proteins which can heterodimerize with each other. These proteins have opposing effects on cell survival when overexpressed in cells, with Bcl-2 blocking and Bax promoting apoptosis. Here we demonstrate that gene transfer-mediated elevations in Bcl-2 protein levels result in a marked increase in the steady-state levels of endogenous p21Bax protein as determined by immunoblotting in the Jurkat T-cell and 697 pre-B-cell leukemia cell lines, but not in several other cell lines including CEM T-cell leukemia, 32D.3 myeloid progenitor, PC12 pheochromocytoma, and NIH-3T3 fibroblasts. Steady-state levels of p21Bax protein were also elevated in the lymph nodes of Bcl-2 transgenic mice in which a BCL-2 transgene is expressed at high levels in B-cells. Northern blot analysis of BCL-2-transfected and control-transfected Jurkat and 697 leukemia cells revealed no Bcl-2-induced alterations in the steady-state levels of BAX mRNAs. In contrast, L-[35S]methionine pulse-chase analysis indicated a marked increase in the half-life (t1/2) of the p21Bax protein in BCL-2-transfected 697 cells compared to control-transfected cells (t1/2 > 24 h versus approximately 4 h), whereas the rate of Bax degradation was unaltered in Bcl-2-transfected CEM cells. The results demonstrate that levels of the proapoptotic p21Bax protein can be post-translationally regulated by Bcl-2, probably in a tissue-specific fashion, and suggest the existence of a feedback mechanism that may help to maintain the ratio of Bcl-2 to Bax protein in physiologically appropriate ranges.
...
PMID:Overexpression of the Bcl-2 protein increases the half-life of p21Bax. 759 1

The BAX gene is a member of the Bcl-2 gene family; it encodes a 21-kDa protein whose association with Bcl-2 is believed to play a critical role in regulating apoptosis. Through analysis of human-hamster somatic cell hybrid DNA and by in situ hybridization to metaphase chromosomes, we have determined that the human BAX gene is located in the q13.3-q13.4 region of human chromosome 19. We have also isolated a BAX cDNA clone in which that part of the mRNA encoded by exon 3 is absent. The skipping of exon 3 and the resultant splicing of exons 2 and 4 maintains the original reading frame and predicts the existence of an interstitially truncated form of the major Bax protein (Bax alpha), termed Bax delta. Unlike two previously described variant forms of Bax alpha (Bax beta and Bax tau), Bax delta retains the functionally critical C-terminal membrane anchor region as well as the Bcl-2 homology 1 and 2 (BH1 and BH2) domains.
...
PMID:Mapping of the human BAX gene to chromosome 19q13.3-q13.4 and isolation of a novel alternatively spliced transcript, BAX delta. 760 85

Recent studies have shown that the Bcl-2 protein suppresses programmed cell death or apoptosis induced by a variety of stimuli including chemotherapeutic drugs. Because estrogen promotes the survival of estrogen-dependent breast cancer cells in vivo, we investigated whether estrogen might regulate levels of Bcl-2 gene expression in an estrogen-responsive human breast cancer cell line. Estrogen receptor-positive MCF-7 human breast cancer cells cultured in the presence of estrogen express the 8.5-kb Bcl-2 mRNA transcript. Depletion of estrogen from the medium results in loss of expression of the mRNA, whereas reexposure to estrogen markedly induces the Bcl-2 transcript. The changes in Bcl-2 mRNA are paralleled by changes in Bcl-2 protein levels. Estrogen-induced increases in Bcl-2 are significantly inhibited by inclusion of the pure antiestrogen ICI 164,384 in the medium. The Bax protein that heterodimerizes with Bcl-2 and promotes cell death is expressed in MCF-7 cells grown in the presence of estrogen and is unaffected by culture in estrogen-free medium. Estrogen depletion doubles the sensitivity of MCF-7 cells to the cytotoxic effects of Adriamycin compared with cells cultured in medium supplemented with estrogen, consistent with a decrease in the Bcl-2 levels. MCF-7 cells treated simultaneously with estrogen and ICI 164,384 exhibit markedly lower resistance to Adriamycin compared with cells treated with estrogen alone. In the absence of estrogen, MCF-7 cells transfected with Bcl-2 expression plasmids display a marked increase in resistance to Adriamycin. In the presence of estrogen, MCF-7 cells expressing Bcl-2 antisense transcripts are rendered twice as sensitive to acute Adriamycin cytotoxicity as a control clone. We conclude that estrogen can promote resistance of estrogen receptor bearing human breast cancer cells to chemotherapeutic drugs through a mechanism that involves regulation of the Bcl-2 proto-oncogene.
...
PMID:Estrogen promotes chemotherapeutic drug resistance by a mechanism involving Bcl-2 proto-oncogene expression in human breast cancer cells. 764 Dec 10

Bax is a homologue of Bcl-2 that promotes apoptosis. Bax protein levels were assessed by immunohistochemical methods in primary tumors derived from 119 women with metastatic breast cancer. These patients had received combination chemotherapy either with a once a month dosage schedule or in 4 weekly divided doses. The BAX immunostaining results were retrospectively compared with overall survival, time to tumor progression (TTP), and response, as well as several laboratory markers. Normal breast epithelium and in situ carcinomas immunostained positively for Bax. Marked reductions in Bax immunostaining were observed in 40 (34%) of 119 evaluable tumors. Reduced Bax correlated with shorter overall survival (median, 8.1 versus 15.7 months; P = 0.04), faster TTP (median, 2.0 versus 6.3 months; P = 0.009), and failure to respond (complete response, partial responses; 6% versus 42%, P = 0.01) in the subgroup of patients who received divided dose therapy. Reduced Bax immunostaining was not significant in the monthly dose group. When the two groups were combined, however, reduced Bax was significantly correlated in univariate analysis with failure to respond (21 versus 43% achieving complete response or partial response; P = 0.02), faster TTP (median, 3.7 versus 9.0 months; P = 0.02), and shorter survival (median, 10.7 versus 17.1 months; P = 0.04). Bax immunostaining was not significantly correlated with tumor histology, S-phase fraction, aneuploidy, p53 HER2, or cathepsin D, but was positively associated with Bcl-2 (P = 0.005). In multivariate analysis (Bax, tumor grade, and treatment group), reduced Bax was strongly associated with faster TTP (P approximately equal to 0.009) and shorter survival (P approximately equal to 0.001). Although highly preliminary, the finding suggest that loss of Bax immunostaining represents a novel prognostic indicator of poor response to chemotherapy and shorter survival in women with metastatic breast cancer, and raise the possibility that the subgroup of women with Bax-negative tumors may benefit from more aggressive therapy.
...
PMID:Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. 767 Dec 62

Upon cytokine withdrawal, interleukin (IL) 6-dependent murine plasmacytoma/hybridoma (myeloma) cells die in a way characteristic of apoptosis. Although gene transfer-mediated elevation in Bcl-2 protein levels has been demonstrated to repress a number of apoptotic death programs, it has been reported that ectopic bcl-2 expression is unable to prolong the survival of IL-6-deprived myeloma cells. In view of the recent identification of Bax as a protein that antagonizes the anti-apoptotic function of Bcl-2, we sought to determine whether the inability of transfected bcl-2 to protect against myeloma cell apoptosis might simply be due to insufficient levels of Bcl-2 protein produced to counteract this inhibitor. We show here that high-level expression of an exogenous bcl-2 gene, introduced into IL-6-dependent B9 myeloma cells via retroviral or bovine papilloma virus-based vectors, is indeed able to suppress apoptotic death following cytokine deprivation, with the extent of protection provided correlating with the amount of Bcl-2 protein synthesized in relation to the amount of endogenous Bax protein present in the cells. Of note, however, we found that IL-6-mediated suppression of B9 apoptosis does not involve induction of endogenous bcl-2 expression but is associated instead with the upregulation of cellular bcl-x mRNA and Bcl-xL protein. These results thus extend the apoptotic death mechanisms that are inhibitable by both bcl-2 and bcl-xL to include that operative in IL-6-dependent cells and suggest that apoptosis in other cell types using the gp130 subunit of the IL-6 receptor might also be bcl-2 regulable or bcl-xL dependent.
...
PMID:Prevention of myeloma cell apoptosis by ectopic bcl-2 expression or interleukin 6-mediated up-regulation of bcl-xL. 775 73

Interactions of the Bcl-2 protein with itself and other members of the Bcl-2 family, including Bcl-X-L, Bcl-X-S, Mcl-1, and Bax, were explored with a yeast two-hybrid system. Fusion proteins were created by linking Bcl-2 family proteins to a LexA DNA-binding domain or a B42 trans-activation domain. Protein-protein interactions were examined by expression of these fusion proteins in Saccharomyces cerevisiae having a lacZ (beta-galactosidase) gene under control of a LexA-dependent operator. This approach gave evidence for Bcl-2 protein homodimerization. Bcl-2 also interacted with Bcl-X-L and Mcl-1 and with the dominant inhibitors Bax and Bcl-X-S. Bcl-X-L displayed the same pattern of combinatorial interactions with Bcl-2 family proteins as Bcl-2. Use of deletion mutants of Bcl-2 suggested that Bcl-2 homodimerization involves interactions between two distinct regions within the Bcl-2 protein, since a LexA protein containing Bcl-2 amino acids 83-218 mediated functional interactions with a B42 fusion protein containing Bcl-2 amino acids 1-81 but did not complement a B42 fusion protein containing Bcl-2 amino acids 83-218. In contrast to LexA/Bcl-2 fusion proteins, expression of a LexA/Bax protein was lethal to yeast. This cytotoxicity could be abrogated by B42 fusion proteins containing Bcl-2, Bcl-X-L, or Mcl-1 but not those containing Bcl-X-S (an alternatively spliced form of Bcl-X that lacks a well-conserved 63-amino acid region). The findings suggest a model whereby Bax and Bcl-X-S differentially regulate Bcl-2 function, and indicate that requirements for Bcl-2/Bax heterodimerization may be different from those for Bcl-2/Bcl-2 homodimerization.
...
PMID:Interactions among members of the Bcl-2 protein family analyzed with a yeast two-hybrid system. 793 47

The protein encoded by the bcl-2 gene is a regulator of programmed cell death and apoptosis. The cell survival-promoting activity of this protein is opposed by Bax, a homologous protein that forms heterodimers with Bcl-2 and accelerates rates of cell death. In this report, the in vivo patterns of bax gene expression were immunohistochemically assessed in the mouse, with a polyclonal antibody raised against a synthetic peptide corresponding to a unique region in the murine Bax protein. Direct comparisons were made with Bcl-2 by using anti-peptide antisera specific for the mouse Bcl-2 protein. The expression of bax was more widespread than bcl-2. For example, Bax immunoreactivity was present in the hepatocytes of the liver, the exocrine pancreas, and the renal tubule epithelial cells whereas Bcl-2 was absent from these tissues. Both the Bax and Bcl-2 proteins were present in several epithelia examined, including the small intestines, colon, breast, prostate, respiratory tract, and skin. The most intense Bax immunostaining was seen in cells located in the base of the crypts of the small intestinal mucosa, consistent with reports of high rates of spontaneous and inducible apoptosis in this region. Bcl-2 immunostaining was completely absent from these cells but was present in the absorptive epithelial cells of the small intestine. In contrast, Bax immunostaining in the colon tended to be stronger in the surface epithelial cells that had advanced up the crypts towards the lumen and that are destined for programmed cell death, whereas Bcl-2 immunoreactivity generally was stronger in the base of the colonic crypts. Similarly, bax expression in the gastric pits of the stomach occurred in a gradient such that higher levels of Bax immunostaining were found in the upper layers of gastric glands than in the lower regions. In addition, strong Bax immunostaining was detected in the androgen-dependent secretory epithelial cells of the prostate, whereas Bcl-2 was limited to the androgen-independent basal cells. Like Bcl-2, Bax was found in the thymic medulla but not the cortex, despite the propensity for immature cortical thymocytes to undergo apoptosis. Unlike Bcl-2, however, Bax immunostaining tended to be more intense in the germinal center lymphocytes of lymph nodes than in the interfollicular lymphocytes, consistent with the high rate of apoptotic cell death in the former.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2. 799 38

Recently, both Bcl-2, which promotes cell survival, and Bax, which promotes cell death, have been implicated as major players in the control of apoptotic pathways, and it has been suggested that the ratio of Bcl-2 and Bax protein controls the relative susceptibility of cells to death stimuli. We have used M1 myeloid leukemia cells and genetically engineered M1 variants as a model system to study apoptosis induced by two distinct apoptotic stimuli. This includes apoptosis induced by activation of wild type p53 function of a temperature sensitive p53 transgene expressed in M1 cells, which do not express endogenous p53, and apoptosis induced by TGF beta 1. It is shown that the kinetics of apoptosis induced by p53 is more rapid than apoptosis induced by TGF beta 1. It is also shown that ectopic expression of Bcl-2, at levels which blocked TGF beta 1-induced apoptosis of M1 cells, delayed, but did not block, p53-induced apoptosis. Both p53 and TGF beta 1 down-regulated endogenous Bcl-2 expression, but only p53 up-regulated Bax expression, where bax has been identified as a p53 immediate early response gene. Thus, the p53-mediated up-regulation of Bax may provide at least a partial explanation for the more rapid rate of apoptosis induced by p53 compared to by TGF beta 1, as well as for the ineffectiveness of ectopoic Bcl-2 to abrogate p53-mediated apoptosis. These findings provide first insights to the molecular mechanisms which mediate p53-induced apoptosis, identifying bax and bcl-2 as p53 regulated genes, and serve as a paradigm of how the intracellular balance of Bcl-2 to Bax is differentially altered by distinct death stimuli.
...
PMID:Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways. 818 78

The p53 tumor suppressor gene product can induce apoptotic cell death through an unknown mechanism. Here we demonstrate that a temperature-sensitive p53 induces temperature-dependent decreases in the expression of the apoptosis-suppressing gene bcl-2 in the murine leukemia cell M1, while simultaneously stimulating increases in the expression of bax, a gene which encodes a dominant-inhibitor of the Bcl-2 protein. Mice deficient in p53 exhibit increases in Bcl-2 and decreases in Bax protein levels in several tissues as determined by immunohistochemical and immunoblot methods. The findings suggest a potential mechanism by which p53 regulates apoptosis, as well as responses to radiation and chemotherapeutic drugs in cancer.
...
PMID:Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. 818 79

1 2 3 4 5 6 7 8 9 10 Next >>