UNIPROT:P10415 - FACTA Search

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

Studies in cell culture systems have indicated that oncogenic forms of Ras can affect apoptosis. Activating mutations of Ras occur in approximately 30% of all human tumors and 50% of colorectal carcinomas. Since these mutations appear at early or intermediate stages in multistep journeys to neoplasia, an effect on apoptosis may help determine whether initiated cells progress towards a more neoplastic state. We have tested the effects of K-rasVal12 on apoptosis in transgenic mice. A lineage-specific promoter was used to direct expression of human K-rasVal12, with or without wild-type (wt) or mutant SV-40 T antigens (TAg), in postmitotic villus enterocytes, the principal cell type of the small intestinal epithelium. Enterocytes can be induced to reenter the cell cycle by TAgWt. Reentry is dependent upon the ability of TAg to bind pRB and is associated with a p53-independent apoptosis. Analyses of K-rasVal12 x TAgWt bi-transgenic animals indicated that K-rasVal12 can enhance this apoptosis threefold but only in cycling cells; increased apoptosis does not occur when K-rasVal12 is expressed alone or with a TAg containing Glu107,108two head right arrow Lys107, 108 substitutions that block its ability to bind pRB. Analysis of bi-transgenic K-rasVal12 x TAgWt mice homozygous for wild-type or null p53 alleles established that the enhancement of apoptosis occurs through a p53-independent mechanism, is not attributable to augmented proliferation or to an increase in abortive cell cycle reentry (compared to TAgWt mice), and is not associated with detectable changes in the crypt-villus patterns of expression of apoptotic regulators (Bcl-2, Bcl-xL, Bak, and Bax) or mediators of epithelial cell-matrix interactions and survival (e.g., alpha5beta1 integrin and its ligand, fibronectin). Coexpression of K-rasVal12 and TAgWt produces dysplasia. The K-rasVal12-augmented apoptosis is unrelated to this dysplasia; enhanced apoptosis is also observed in cycling nondysplastic enterocytes that produce K-rasVal12 and a TAg with a COOH-terminal truncation. The dysplastic epithelium of K-rasVal12 x TAgWt mice does not develop neoplasms. Our results are consistent with this finding: (a) When expressed in initiated enterocytes with a proliferative abnormality, K-rasVal12 facilitates progression to a dysplastic phenotype; (b) by diminishing cell survival on the villus, the oncoprotein may impede further progression; and (c) additional mutations may be needed to suppress this proapoptotic response to K-rasVal12.
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PMID:Bi-transgenic mice reveal that K-rasVal12 augments a p53-independent apoptosis when small intestinal villus enterocytes reenter the cell cycle. 921 90

Erythropoietin (EP) is required by late-stage erythroid progenitor cells to prevent apoptosis. Several lines of evidence suggest that it is this action of EP that regulates erythrocyte production in vivo. To study the control of apoptosis in mouse and human erythroblasts, the expression of members of the Bcl-2 family of proteins and the expression and activation of the apoptosis-linked cysteine protease Yama/CPP32/apopain were examined. These proteins have been implicated as regulators of apoptosis in several cell models. The Bcl-2 family members analyzed were Bcl-2, Bcl-X, Bax, Bad, Bak, A1, and Mcl-1. Bcl-X expression in proerythroblasts was highly EP-dependent. Bcl-X was strongly increased during the terminal differentiation stages of human and mouse erythroblasts, reaching maximum transcript and protein levels at the time of maximum hemoglobin synthesis. This increase in Bcl-X expression led to an apparent level of approximately 50 times the level in proerythroblasts. In contrast, neither mouse nor human erythroblasts expressed Bcl-2 transcript or protein. Bax and Bad proteins remained relatively constant throughout differentiation, but diminished near the time of enucleation. Bak protein was present in early erythroblasts, but diminished progressively during differentiation. EP deprivation in both mouse and human erythroblasts led to activation of the cysteine protease, apopain, as was indicated by cleavage of the proenzyme into its proteolytically active fragments. Apopain activation was detectable within 2 hours of EP deprivation in mouse erythroblasts. These findings suggest an important role for Bcl-X in late erythroid differentiation and for apopain in apoptosis of erythroblasts caused by deprivation of EP.
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PMID:The roles of Bcl-X(L) and apopain in the control of erythropoiesis by erythropoietin. 922 63

The radiosensitivity of proliferating crypt epithelial cells makes the gut a major limiting factor in the use of radiotherapy for treatment of abdominal cancers. As post-mitotic epithelial cells migrate from mouse small intestinal crypts to the base of adjacent villi, they rapidly lose their ability to undergo apoptosis in response to ionizing irradiation (IR). To determine whether this radioresistance reflects withdrawal from the cell cycle, we used a lineage-specific promoter to direct expression of wild type Simian virus 40 T antigen (SV40 TAg(Wt)) to villus, but not crypt, enterocytes in FVB/N transgenic mice. SV40 TAg(Wt) induced, pRB-dependent, re-entry into the cell cycle is not associated with the acquisition of IR-stimulated apoptosis 4 h or 24 h after 6 Gy or 12 Gy of gamma-irradiation. Co-expression of SV40 TAg(Wt) and K-ras(val12) produces dysplasia in cycling villus enterocytes but no shift towards apoptotic responsiveness to IR. These findings suggest that the radioresistance of villus enterocytes is not simply due to their cell cycle arrest and may be a reflection of their microenvironment. Remarkably, reentry of villus enterocytes to the cell cycle increases the radiosensitivity of the crypt epithelium without changing Bcl-2, Bcl-xL, Bak, or Bax expression. This effect is only manifest after IR and, based upon results obtained with mutant SV40 TAgs, depends upon reaching a critical level of proliferation in villus enterocytes. Like the normal crypt response to IR, the villus-derived enhancement of IR-stimulated crypt apoptosis is associated with an induction of p53 and Raf-1, and is dependent upon p53. Unlike the normal crypt response to IR, the p53 induction involves cells distributed throughout the crypt and the apoptotic response is not confined to the lower half of the crypt. These results indicate that signals initiated by cycling enterocytes can be transmitted to the crypt epithelium to induce p53 and influence their IR-induced apoptosis. Understanding the underlying signaling pathways may provide clues about how to modify a normal crypt's radiosensitivity for therapeutic benefit.
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PMID:gamma-Ray-induced apoptosis in transgenic mice with proliferative abnormalities in their intestinal epithelium: re-entry of villus enterocytes into the cell cycle does not affect their radioresistance but enhances the radiosensitivity of the crypt by inducing p53. 924 49

To facilitate the creation of Bak knockout mice and the further analysis of this Bcl-2 family member, we have isolated and sequenced the complete mouse Bak cDNA. The cDNA is 2 kb long and shares an overall nucleotide identity to the human Bak cDNA of 62%. The mouse Bak protein is 208 amino acids long with a predicted molecular weight of 23 kDa. The mouse Bak mRNA could be detected in all mouse tissues examined. In addition we mapped the murine bak gene. It consists of six exons spanning about 10 kb on chromosome 17B. The 5' region of the murine bak gene is unmethylated on the dinucleotide CpG in the area around exon 1. Furthermore, it contains potential binding sites for transcription factors such as Sp1 and c-Myb.
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PMID:Gene structure, cDNA sequence, and expression of murine Bak, a proapoptotic Bcl-2 family member. 929 36

The Bcl-2 family of proteins regulate apoptosis, some antagonizing cell death and others facilitating it. It has recently been demonstrated that Bcl-2 not only inhibits apoptosis but also restrains cell cycle entry. We show here that these two functions can be genetically dissociated. Mutation of a tyrosine residue within the conserved N-terminal BH4 region had no effect on the ability of Bcl-2 or its closest homologs to enhance cell survival and did not prevent heterodimerization with death-enhancing family members Bax, Bak, Bad and Bik. Neither did this mutation override the growth-inhibitory effect of p53. However, on stimulation with cytokine or serum, starved quiescent cells expressing the mutant proteins re-entered the cell cycle much faster than those expressing comparable levels of wild-type proteins. When wild-type and Y28 mutant Bcl-2 were co-expressed, the mutant was dominant. Although R-Ras p23 has been reported to bind to Bcl-2, no interaction was detectable in transfected cells and R-Ras p23 did not interfere with the ability of Bcl-2 to inhibit apoptosis or cell cycle entry. These observations provide evidence that the anti-apoptotic function of Bcl-2 is mechanistically distinct from its inhibitory influence on cell cycle entry.
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PMID:The anti-apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry. 930 7

Bik is a potent pro-apoptotic protein, which complexes with various anti-apoptotic proteins such as Bcl-2, Bcl-xL, 19-kDa adenovirus E1B, and EBV-BHRF1. The mechanism by which Bik promotes cell death is not known. It shares a conserved domain, BH3, with other pro-apoptotic proteins, Bax, Bak, Bid, and Hrk, and certain anti-apoptosis proteins such as Bcl-2 and Bcl-xL. Mutations within the BH3 domain of Bik abrogate its ability to induce cell death and to complex with anti-apoptosis proteins. This result is consistent with the hypothesis that Bik may promote cell death by complexing with and antagonizing the activity of endogenous cellular anti-apoptosis proteins such as Bcl-2 and Bcl-xL. To elucidate the relationship between protein complex formation and induction of cell death, we have identified the minimal sequences of Bik, from a library of N-terminal and C-terminal deletion mutants, required for interaction with Bcl-2 and Bcl-xL and for inducing efficient cell death. Two-hybrid analysis in yeast and immunoprecipitation analysis of proteins expressed in mammalian cells indicate that a 52-amino acid region (amino acids 43-94) of Bik, encompassing the BH3 domain, is sufficient for efficient heterodimerization with Bcl-2 and Bcl-xL. Protein interaction studies further reveal that an 18-amino acid region, encompassing the BH3 domain (residues 57-74), constitutes the core heterodimerization domain. Functional analysis indicates that a Bik deletion mutant expressing residues 43-120, which efficiently heterodimerizes with the anti-apoptosis proteins Bcl-2 and Bcl-xL, is defective in eliciting cell death. In contrast, a mutant expressing additional C-terminal sequences (amino acids 43-134) interacts with the survival proteins and elicits efficient cell death. Our results suggest that for Bik-mediated cell death, the heterodimerization activity encoded by the BH3 domain alone is insufficient and raise the possibility that Bik may induce cell death autonomous of heterodimerization with survival proteins such as Bcl-2 and Bcl-xL.
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PMID:Functional dissection of the pro-apoptotic protein Bik. Heterodimerization with anti-apoptosis proteins is insufficient for induction of cell death. 930 12

Treatment of human promyelocytic leukemia HL-60 cells with phorbol esters ultimately induces the differentiation of these cells along the monocyte/macrophage lineage, whereas treatment with retinoic acid or DMSO induces granulocytic/neutrophillic differentiation. In this study, we demonstrate the disparate fates of HL-60 cells treated with the phorbol ester 12,13-phorbol dibutyric acid (PDBu) or DMSO. After DMSO treatment, HL-60 cells eventually died via apoptosis, whereas the viability of PDBu-treated cells was not affected during the same interval. The levels of the apoptosis effector proteins Bak and Bad were enhanced, whereas there was a slight down-regulation of the apoptosis suppressor protein Bcl-2 after treatment of the cells with PDBu and DMSO. Treatment with DMSO resulted in the elevation of the apoptosis effector Bax, whereas treatment with PDBu did not significantly alter the levels of this protein. However, treatment of HL-60 cells with PDBu induced the rapid expression of the apoptosis suppressor protein Bcl-xL, whereas the expression of this protein remained unaltered in DMSO-treated cells. The generality of this finding was confirmed by the induction of Bcl-xL in human myeloid U-937 cells, human peripheral blood monocytes exposed to phorbol ester, and mouse thioglycollate-activated and resident peritoneal macrophages. PDBu-treated HL-60 cells remained viable for 7 days and thereafter began to die via apoptosis, with a concomitant down-regulation of Bcl-xL. In conclusion, we propose that Bcl-xL expression is associated with differentiation and survival of hematopoietic cells along the monocyte/macrophage lineage.
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PMID:Monocytic differentiation of HL-60 promyelocytic leukemia cells correlates with the induction of Bcl-xL. 934 86

Carriage of the bacterium H. pylori in the human stomach is associated with evidence of increased epithelial cell apoptosis. This may be of significance in the etiology of gastritis, peptic ulcers, and neoplasia. The ability of H. pylori to directly induce epithelial apoptosis was examined in vitro by fluorescence and electron microscopy, flow cytometry, and DNA fragmentation ELISA. The induction of apoptosis by H. pylori was time and concentration-dependent and inhibited by preventing direct bacterial-epithelial cell contact. Apoptosis was accompanied by increased expression of Bak, with little change in expression of other Bcl-2 family proteins. The expression of Bak was also increased in gastric biopsies from patients colonized by H. pylori. Thus, H. pylori induces gastric epithelial cell apoptosis, by a Bak-dependent pathway.
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PMID:Apoptosis in gastric epithelial cells is induced by Helicobacter pylori and accompanied by increased expression of BAK. 934 82

In the intracellular death program, hetero- and homodimerization of different anti- and pro-apoptotic Bcl-2-related proteins are critical in the determination of cell fate. From a rat ovarian fusion cDNA library, we isolated a new pro-apoptotic Bcl-2 gene, Bcl-2-related ovarian killer (Bok). Bok had conserved Bcl-2 homology (BH) domains 1, 2, and 3 and a C-terminal transmembrane region present in other Bcl-2 proteins, but lacked the BH4 domain found only in anti-apoptotic Bcl-2 proteins. In the yeast two-hybrid system, Bok interacted strongly with some (Mcl-1, BHRF1, and Bfl-1) but not other (Bcl-2, Bcl-xL, and Bcl-w) anti-apoptotic members. This finding is in direct contrast to the ability of other pro-apoptotic members (Bax, Bak, and Bik) to interact with all of the anti-apoptotic proteins. In addition, negligible interaction was found between Bok and different pro-apoptotic members. In mammalian cells, overexpression of Bok induced apoptosis that was blocked by the baculoviral-derived cysteine protease inhibitor P35. Cell killing induced by Bok was also suppressed following coexpression with Mcl-1 and BHRF1 but not with Bcl-2, further indicating that Bok heterodimerized only with selective anti-apoptotic Bcl-2 proteins. Northern blot analysis indicated that Bok was highly expressed in the ovary, testis and uterus. In situ hybridization analysis localized Bok mRNA in granulosa cells, the cell type that underwent apoptosis during follicle atresia. Identification of Bok as a new pro-apoptotic Bcl-2 protein with restricted tissue distribution and heterodimerization properties could facilitate elucidation of apoptosis mechanisms in reproductive tissues undergoing hormone-regulated cyclic cell turnover.
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PMID:Bok is a pro-apoptotic Bcl-2 protein with restricted expression in reproductive tissues and heterodimerizes with selective anti-apoptotic Bcl-2 family members. 935 61

Bak has been shown to both promote apoptosis and to inhibit cell death while two other members of the Bcl-2 family of proteins, Bcl-XL and Bcl-2 delay apoptosis induced by various stimuli including chemotherapeutic agents. We generated clones with stable expression of Bak wild-type (wt) and Bak with its BH3 (delta78-86) domain deleted (deltaBH3) in FL5.12 cells or FL5.12 cells expressing either Bcl-XL or Bcl-2 to determine if Bak could accelerate apoptosis and antagonize the death repressor activity of Bcl-XL and Bcl-2 during chemotherapy-induced apoptosis. We found that Bak accelerated cell death in FL5.12 cells treated with etoposide, fluorouracil or taxol. In FL5.12 cells expressing Bcl-XL and Bak wt or Bak deltaBH3, both Bak wt or Bak deltaBH3 were able to antagonize the protective effect of Bcl-XL when treated with etoposide or fluorouracil. Bak wt or Bak deltaBH3 were also able to abrogate the protective effect of Bcl-2 in cells expressing Bcl-2 and Bak wt or Bak deltaBH3 when challenged by etoposide or fluorouracil. Immunoprecipitation studies revealed that deletion of BH3 disrupted heterodimerization between Bak and Bcl-XL and that both Bak wt and Bak deltaBH3 failed to interact with Bcl-2. These results demonstrate that Bak does not require its BH3 domain to promote apoptosis in stably transfected cells. Furthermore, Bak can accelerate chemotherapy-induced cell death independently of its heterodimerization with Bcl-XL and Bcl-2.
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PMID:Bak can accelerate chemotherapy-induced cell death independently of its heterodimerization with Bcl-XL and Bcl-2. 936 54

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