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)

Interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF) induce DNA synthesis and suppress apoptosis of hematopoietic cells. IL-3/GM-CSF exert pleiotropic functions by activating multiple signaling cascades through distinct domains of the common receptor subunit. As we previously reported, the Ras signaling pathway plays a pivotal role in suppressing apoptotic death rather than stimulating DNA synthesis in IL-3 dependent hematopoietic cells. In order to clarify the molecular basis of Ras-induced cell survival, we investigated the effect of Ras activation on the expression of Bcl-2 and its related molecules. Activation of the Ras pathway by using an inducible oncogenic Ras resulted in the rapid up-regulation of bcl-2 and bcl-xL, and the level of expression was nearly equivalent to that observed in growing cells. On the other hand, expression of bax, an antagonistic bcl-2 homologue, was not affected by oncogenic Ras or IL-3-deprivation. Thus, the Ras pathway regulates the expression of Bcl-2 and its related survival protein, and this appears to underlie the mechanism by which IL-3/GM-CSF inhibit apoptosis through activation of the Ras pathway.
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PMID:Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells. 778 65

Bcl-2 and Bax have recently been identified as putative repressor and effector proteins respectively, in the cell death program of growth factor-deprived haematopoietic cell lines. Overexpression of bcl-2 in neuronal cell culture prevents apoptosis induced by removal of neurotrophic factors. In the present in vivo study the expression of bcl-2 and bax mRNA has been investigated in dorsal root ganglia of young and adult rats using polymerase chain reaction. A high constitutive expression was observed for both genes in control ganglia. Unilateral transection of the sciatic nerve led to a dramatic decrease in bcl-2 mRNA levels in ganglia of young animals within 5 days following nerve lesion and a partial recovery thereafter. In contrast, the decline in bcl-2 mRNA was much less pronounced in axotomized ganglia of adults. The amount of bax transcripts did not change significantly in ganglia of both young and adult rats up to 20 days after nerve injury. The decrease in bcl-2 expression in dorsal root ganglia may be part of the molecular mechanism leading to neuronal cell death after axotomy-induced deprivation of neurotrophic factors. The age-dependent decline in the ratio of bcl-2 to bax gene products may explain the greater susceptibility of immature neurons to apoptosis.
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PMID:Differential expression of bcl-2 and bax mRNA in axotomized dorsal root ganglia of young and adult rats. 785 28

DNA-damaging agents such as ionizing radiation (IR) activate the tumor suppressor p53 and in some cases can cause apoptosis. M1 cells, which do not express the endogenous tumor suppressor gene p53, undergo apoptosis following activation of a temperature sensitive p53 transgene, where it has been shown that bax, an important mediator of apoptosis, is a p53 target gene (Selvakumaran et al, Oncogene 9, 1791-8, 1994). Since p53 can function as a transcription factor after activation by IR, the genetic response to this stress was examined in a panel of human cells with defined p53 status. Like the p53-regulated gene gadd45, bax was rapidly induced, as measured by increased mRNA levels, in the p53 wt (wild type) human myeloid line ML-1, and it was not induced in cells lacking functional p53. However, unlike other p53-regulated genes, bax was only induced in p53 wt cells in which IR also triggered apoptosis. In the case of bcl2, which opposes bax function, mRNA levels were reduced in ML-1 cells after IR. Thus, bax appears to be an unique p53-regulated gene in that its induction by IR not only requires functional p53 but also requires that the cells be apoptosis "proficient."
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PMID:Induction of bax by genotoxic stress in human cells correlates with normal p53 status and apoptosis. 797 Jul 35

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)
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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.
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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.
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PMID:Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. 818 79

The ability of Bcl-2 to inhibit apoptotic cell death is well established. Several homologues of the bcl-2 gene, such as bax, bcl-x or mcl-1, have recently been identified. Like Bcl-2, both Bcl-XL and Mcl-1 appear to function as repressors of apoptotic cell death, whereas Bax facilitates it, indicating possible interactions among them in the control of cellular survival. To investigate the in vivo role of expression of bcl-2 gene family products, immunoblot analysis using corresponding specific antisera was performed for peripheral blood cells and some lymphoid tissues in humans. We demonstrated that all Bcl-2 family proteins were expressed at various levels in hematolymphoid cell subpopulations isolated from peripheral blood, tonsil, spleen and thymus. Lymphoid expression of Bcl-2 family proteins tended to increase following activation, but declined with time in culture. Loss of Bcl-2 in cultured lymphoid cells was especially marked. Sole expression of Bax, but not other members of the Bcl-2 family, was observed on neutrophils, seemingly reflecting their shortest life-span among blood leukocytes. The results support the notion that a balance of expression of Bcl-2 family proteins may regulate the life and death of hematolymphoid cells at different stages of cell differentiation and activation.
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PMID:Immunoblot analysis of cellular expression of Bcl-2 family proteins, Bcl-2, Bax, Bcl-X and Mcl-1, in human peripheral blood and lymphoid tissues. 858 80

Following 10-min cardiac arrest and resuscitation, male Sprague-Dawley rats developed posthypoxic myoclonus. This phenomenon peaked at 14 days and disappeared by 45 days after cardiac arrest. The mechanisms for the initial dysfunction and later restoration of motor function are not completely known. In the present study, involvement of Bcl-2 and Bax in these phenomena was investigated. In the frontoparietal cortex, both bcl-2 and bax mRNA levels were significantly increased 1, 3, 7, 14, and 28 days postresuscitation. bax mRNA levels continued to be high 45 days postcardiac arrest, whereas bcl-2 mRNA levels were returned to control levels. The apoptotic cells were found in layers IV to VI of the frontoparietal cortex of rats 3 days postcardiac arrest. These results indicate that after cardiac arrest, the initial rise of Bax levels may mediate apoptosis and neurodegeneration in the rat brain. At later time points, increased levels of Bcl-2 may contribute to recovery of motor function in posthypoxic rats.
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PMID:Expression of Bcl-2 and Bax in the frontoparietal cortex of the rat following cardiac arrest. 859 81

The E1B 19K protein is a potent apoptosis inhibitor and the putative adenovirus Bcl-2 homolog. To investigate the mechanism of apoptosis regulation, 19K-interacting cellular proteins were identified using the yeast two-hybrid system, and Bax was one of seven 19-K interacting clones. Residues 50-78 of Bax containing a conserved region designated Bcl-2 homology region 3 (BH3) were sufficient for specific binding to both the E1B 19K and Bcl-2 proteins. The Bax-E1B 19K interaction was detectable in vitro and in lysates from mammalian cells, and Bax expression antagonized E1B 19K protein function. bax mRNA and protein levels were p53-inducible with kinetics identical to that of p21/Waf-1/Cip-1, and E1B 19K and Bcl-2 expression did not affect Bax or p21/Waf-1/Cip-1 accumulation. In cells where p53 was mutant, Bax expression induced apoptosis, suggesting that Bax was sufficient for apoptosis, and acted downstream of p53. p53 may simultaneously activate the transcription of genes required for both growth arrest (p21/Waf-1/Cip-1) and death (bax), and E1B 19K and Bcl-2 may act distally and function through interaction with and antagonism of Bax to prevent apoptosis. With the death pathway disabled, induction of growth arrest by p53 can then be manifested.
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PMID:The E1B 19K protein blocks apoptosis by interacting with and inhibiting the p53-inducible and death-promoting Bax protein. 860 29

Our previous data have shown that isolated leukemic cells from progressive chronic lymphocytic leukemia (B-CLL) patients respond to growth stimulation in vitro and express high levels of p53, immunoreactive with the configuration-specific antibody PAb 240. We have now analyzed the in vitro survival of B-CLL cells in relation to Bcl-2, Bax alpha and p53 expression and compared this with the clinical progression of the disease. Leukemic cells from patients with progressive disease demonstrated higher in vitro survival, compared with non-progressive B-CLL and normal B cells. All cells were sensitive to treatment with a combination of glucocorticoid and cAMP. Bcl-2 protein levels were not related to clinical progression, as measured by flow cytometry. Competitive PCR showed that Bcl-2 mRNA was over-expressed in most of the B-CLL samples and that p53 mRNA expression was similar between B-CLL groups and normal values and thus not related to clinical progression. However, since Bax alpha expression was lower in progressive than in non-progressive patients, the Bcl-2/Bax alpha ratio at the mRNA level was significantly higher in the progressive group. Our data suggest that the Bcl-2/Bax alpha ratio is important for the regulation of B-CLL cell survival, that p53 over-expression in progressive B-CLL is the result of post-transcriptional modifications and that a directed PKA activation may potentiate the cytolytic effect of glucocorticoids in vivo.
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PMID:Bcl-2, Bax and p53 expression in B-CLL in relation to in vitro survival and clinical progression. 860 78


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