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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 functions to repress apoptosis by regulation of genes which encode proteins required for programmed cell death and by interference with peroxidative damage. We investigated the interrelationship between expression of bcl-2 and regulation of transcription factor DNA binding activities in the 2B4 T cell hybridoma and IL-2-dependent CTLL T cell line. Over-expression of bcl-2 in 2B4 resulted in enhanced basal levels of activator protein (AP)-1, octamer binding factor (Oct)-1, lymphoid enhancer binding factor (LEF)-1, RelA-p50 and NF-kappa B p50-p50 DNA binding activities. After apoptotic signaling, down-regulation of AP-1, NF-AT and Oct-1 binding activities was observed in control 2B4 and CTLL, whereas suboptimal, but higher, levels of these transcription factors were found in bcl-2-transfected cells, potentially promoting cell survival. Furthermore, after apoptotic signaling, expression of bcl-2 led to differential changes of NF-kappa B levels, resulting in a decrease in RelA-p50 and an increase in NF-kappa B p50-p50, altering the ratio of these DNA binding activities such that now p50-p50 markedly predominated in both 2B4-Bcl-2 and CTLL-Bcl-2. Apoptotic signaling in the presence or absence of Bcl-2 resulted in induction of the RelB-p50 heterodimer in 2B4. The changes in NF-kappa B/Rel levels raise the possibility that this family of transcription factors may play an important role in the regulation of apoptosis.
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PMID:Pleiotropic effects of Bcl-2 on transcription factors in T cells: potential role of NF-kappa B p50-p50 for the anti-apoptotic function of Bcl-2. 858 69

The endogenous expression of p53 and p53-regulated genes has been examined in a thymidylate synthase-deficient colon carcinoma cell line (TS-) and a derived mutant clone (Thy4) that exhibit acute or delayed apoptotic responses, respectively, when released from G0 synchrony under conditions of dThd starvation. These cell clones demonstrate heterozygosity in p53, thereby expressing one wt allele and one with an A-->C point mutation at codon 240. Following release from G0, upregulated expression of both alleles occurred. During apoptosis in TS-, a wtp53 phenotype was expressed and in Thy4 during cytostasis, a mp53 phenotype was manifested, as determined from the ratios of wtp53/mp53 proteins, transactivation of p50-2 (a wtp53-responsive CAT reporter construct) and the endogenous expression of MDM2. Neither cytotoxicity nor cytostasis correlated with expression of p21Waf1/Cip1 Thy4 cells sustained accumulation of high levels of Bax in a wtp53-independent and dThd-independent manner and survival was associated with upregulated expression of Bcl-2. In contrast, Bax expression decreased in TS- during apoptosis, except in a highly resistant subpopulation that retained high levels of Bax. Data suggest that resistant cells (Thy4) can sustain high Bax expression and that Bcl-2 is upregulated in response to an apoptotic stimulus due to the absence of negative regulation by wtp53.
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PMID:Acute and delayed apoptosis induced by thymidine deprivation correlates with expression of p53 and p53-regulated genes in colon carcinoma cells. 866 31

In the study presented here, we investigated the possible interactions between CD95 (Fas/APO-1) and Bcl-2 by studying the effects of Bcl-2 on the modulation of cellular pathways activated by CD95 using HeLa cells as a model system. We report that stable expression of Bcl-2 in HeLa cells is associated with multiple phenotypic changes. Treatment of HeLa cells with anti-CD95 monoclonal antibody (mAb) resulted in preferential degradation of lamin B compared with lamins A and C. Significant lamin B degradation was detected as early as 1 h after anti-CD95 mAb treatment. In contrast, lamins A and C as well as actin remained unchanged until 4 h after treatment with anti-CD95 mAb, a time point that correlated with the period of DNA fragmentation. These results indicate that selective degradation of lamin B is an early cellular event in response to activation of the CD95 pathway and that it precedes DNA fragmentation. Overexpression of Bcl-2 resulted in prevention of lamin B degradation and DNA fragmentation into oligonucleosome fragments in response to the apoptotic signal by anti-CD95 mAb. In addition, in Bcl-2-overexpressing cells that were protected against apoptosis, anti-CD95 mAb-induced cleavage of poly(ADP-ribose) polymerase was completely blocked. Overexpression of Bcl-2 also resulted in restoration of the CD95-mediated signaling pathway involving activation of the transcription factor NF-kappaB (p50/RelA). These findings suggest that Bcl-2 prevents apoptosis in part by preventing the degradation of major nuclear polypeptides such as lamin B and poly(ADP-ribose) polymerase. In addition, our results demonstrate that CD95-mediated signaling involves activation of NF-kappaB (p50/RelA).
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PMID:Bcl-2 prevents CD95 (Fas/APO-1)-induced degradation of lamin B and poly(ADP-ribose) polymerase and restores the NF-kappaB signaling pathway. 893 96

TCR-mediated activation of T cell hybridomas induces programmed cell death by a Fas-dependent pathway. We now show that costimulation of 2B4 cells, in the absence or presence of transgenic Bcl-2, with anti-CD3 epsilon and forskolin, an activator of cAMP signaling, resulted in antagonism of Fas-dependent activation-induced cell death that was always accompanied by selective downregulation of the nuclear levels of NF-kappa B p65-p50 (RelA-p50) transcription factor. Forskolin not only inhibited activation-induced cell death and NF-kappa B activation, but also suppressed expression of Fas and Fas ligand (Fas-L). Furthermore, NF-kappa B p65 antisense oligonucleotide down-regulated nuclear levels of NF-kappa B, inhibited cell surface expression of Fas-L and apoptosis of 2B4. Collectively, these finding demonstrate a potential role of NF-kappa B in the regulation of activation-induced apoptosis in T lymphocytes.
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PMID:Regulation of Fas-dependent activation-induced T cell apoptosis by cAMP signaling: a potential role for transcription factor NF-kappa B. 918 60

The Bcl-2 oncoprotein is a key regulator of apoptosis and the Bag-1 protein interacts with Bcl-2 and cooperates with Bcl-2 to suppress apoptosis. The human Bag-1 cDNA is essentially identical with a previously described cDNA encoding RAP46, which interacts with activated steroid hormone receptors. However, there is considerable confusion over the structure of Bag-1/RAP46 proteins and their relationship to endogenous Bag-1 proteins. Here we have characterized Bag-1 expression in mammalian cells. We demonstrate that, in addition to the previously identified 32 kDa murine and 36 kDa human Bag-1 proteins, cells express a second 50 kDa Bag-1 isoform. In some murine cell lines p50 is expressed at the same level as p32 Bag-1, and p50 and p32 Bag-1 proteins have distinct subcellular localizations, suggesting that they are functionally distinct. The published mouse Bag-1 cDNA is partial, and sequencing of additional murine Bag-1 RNA 5' sequences demonstrated that human and murine Bag-1 cDNAs contain longer open reading frames than originally suspected. We determined which open reading frames gave rise to the Bag-1 isoforms in human cells. Surprisingly, translation of neither protein initiated at the first in-frame methionine, and cells do not express Bag-1/RAP46 proteins with the previously proposed structures; p50 Bag-1 initiates at an upstream CUG codon, whereas p36 Bag-1 initiates at a downstream AUG codon. Therefore, cells express two differently localized Bag-1 isoforms generated by alternative translation initiation, and Bag-1 proteins may play a dual role in regulating apoptosis and steroid hormone-dependent transcription.
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PMID:Mammalian cells express two differently localized Bag-1 isoforms generated by alternative translation initiation. 939 24

Previously, a Bcl-2-interacting protein, BAG-1, was cloned from mouse cells and was shown to interact with several other proteins and to be important for inhibition of apoptosis. Human BAG-1 (hBAG-1) cDNA, recently isolated by us and two other groups, has been shown to be identical to a hormone receptor-binding protein, RAP46. However, different molecular masses of hBAG-1 protein products were noted by these three groups. Here we demonstrated that hBAG-1 protein was expressed as four isoforms, designated p50, p46, p33 and p29, with apparent molecular masses of 50 kDa, 46 kDa, 33 kDa and 29 kDa, respectively. Deletion, site-directed mutagenesis and in vitro transcription/translation analysis showed that the four protein products of hBAG-1 were expressed by alternative initiation from four different start codons through a leaky scanning mechanism. Furthermore, we demonstrated that the distinct forms of hBAG-1 have different subcellular localizations, suggesting that they may have distinct functions in the cells. Characterization of hBAG-1 RNA and protein also showed that hBAG-1 was overexpressed in human cervical, breast and lung cancer cell lines. Taken together, these data clarify the conflicting observations reported in the literature and suggest that hBAG-1 is expressed as four forms of protein products, which may play a differential role in apoptosis and oncogenesis of human cells.
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PMID:Human BAG-1/RAP46 protein is generated as four isoforms by alternative translation initiation and overexpressed in cancer cells. 974 77

We characterized kinetic and biochemical changes during glucocorticoid (GC)-induced apoptosis of immature CD8+CD4+ double-positive (DP) thymocytes. A GC analog dexamethasone (Dex) induced rapid apoptotic commitment and a transient up-regulation of the NF-kappaB/RelA-p50-binding activity in DP cells. This required an early activation of proteasome, as judged by the ability of a specific proteasomal inhibitor, lactacystine, to delay apoptosis and to suppress Dex-dependent NF-kappaB activation. Dex-induced apoptotic commitment was preceded by the rapid (3 h) cleavage of both a typical caspase substrate, poly(ADP-ribose) polymerase (PARP), and of nuclear transcription factors AP-1, NF-kappaB p50-p50 and NUR-77. By contrast, phorbol myristate acetate (PMA) and/or ionomycin-induced apoptosis had much slower kinetics, were preceded by an early increase of NF-kappaB/RelA-p50, AP-1 and NUR-77 activities, and were insensitive to proteasome inhibition. Both the transgenic Bcl-2 and zVAD-fmk, an inhibitor of caspases, affected all features of Dex-induced apoptosis in a similar fashion, by inhibiting cell death and PARP cleavage, and by stabilizing AP-1, NF-kappaB p50-p50 and NUR-77 levels. Furthermore, Bcl-2 prevented Dex-induced RelA-p50 activation. However, a higher gene dosage of the transgenic Bcl-2 was required for protection against Dex, compared to the PMA and/or ionomycin-induced apoptosis. These findings highlight the unique mechanistic features of GC-induced apoptosis.
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PMID:Biochemical and kinetic characterization of the glucocorticoid-induced apoptosis of immature CD4+CD8+ thymocytes. 988 1

BAG-1 is an antiapoptotic protein that binds to and enhances the antiapoptotic activity of Bcl-2. It binds several growth factor and hormone receptors and modulates their function. BAG-1 was also shown recently to be expressed as four protein isoforms, p50, p46, p33, and p29, through alternative translation initiation. Although many apoptosis-associated genes have been linked to oncogenesis of human breast cancer, the role of BAG-1 has not been fully elucidated. In this study, we examined the expression of BAG-1 RNA or protein isoforms and its interacting antiapoptotic proteins, Bcl-2 and BcI-X(L), in breast normal and tumor cell lines and tissues by Northern or Western blot analysis. We provide convincing evidence that both BAG-1 RNA and protein are overexpressed in human breast cancer cell lines. More importantly, we found that the expression of two isoforms of BAG-1, p46 and p33, was also much higher in breast primary tumors. The expression of Bcl-2 and Bcl-X(L) correlated with that of BAG-1 in breast normal and carcinoma cell lines but not tissues. Our study suggests that BAG-1 isoforms may serve as a molecular marker, independent of Bcl-2 and Bcl-X(L), for human breast cancer.
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PMID:Differential expression of antiapoptotic gene BAG-1 in human breast normal and cancer cell lines and tissues. 1043 86

Bcl-2 can suppress apoptosis by controlling genes that encode proteins required for programmed cell death and by interference with peroxidative damage. Overexpression of Bcl-2 in NIH3T3 cells can prevent GSNO-induced (S-nitrosoglutathione-induced) apoptosis. The experimental results indicated that activation of NF-kappaB by GSNO is involved in inducing apoptosis. Surprisingly, we found that Bcl-2 delayed the release of IkB by formation of a Bcl-2-NF-kappaB complex (p50-p65-IkappaB) in the cytoplasm during cell apoptosis. Furthermore, a novel Bcl-2-p50 complex was found in the nucleus. These features were only observed in Bcl-2-transfected cells but not in the parental NIH3T3 cells. Overexpression of Bcl-2 suppressed the levels of c-myc, a target gene of NF-kappaB, and influenced the DNA-binding activity of NF-kappaB during GSNOinduced apoptosis. We suggest that the Bcl-2-p50 complex inhibits NF-kappaB DNA-binding activity by competing with the p65-p50 heterodimer for the DNA-binding site in the nucleus. Finally, it has been demonstrated that the anti-apoptotic potential of Bcl-2 may be attributed to its complexing with p50 in the nucleus that leads to blockage of nuclear gene expression.
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PMID:Suppression of transcription factor NF-kappaB activity by Bcl-2 protein in NIH3T3 cells: implication of a novel NF-kappaB p50-Bcl-2 complex for the anti-apoptotic function of Bcl-2. 1072 20

B lymphocyte stimulator (BLyS) is a newly identified monocyte-specific TNF family cytokine. It has been implicated in the development of autoimmunity, and functions as a potent costimulator with antiimmunoglobulin M in B cell proliferation in vitro. Here we demonstrate that BLyS prominently enhances the humoral responses to both T cell-independent and T cell-dependent antigens, primarily by attenuation of apoptosis as evidenced by the prolonged survival of antigen-activated B cells in vivo and in vitro. BLyS acts on primary splenic B cells autonomously, and directly cooperates with CD40 ligand (CD40L) in B cell activation in vitro by protecting replicating B cells from apoptosis. Moreover, although BLyS alone cannot activate the cell cycle, it is sufficient to prolong the survival of naive resting B cells in vitro. Attenuation of apoptosis by BLyS correlates with changes in the ratios between Bcl-2 family proteins in favor of cell survival, predominantly by reducing the proapoptotic Bak and increasing its prosurvival partners, Bcl-2 and Bcl-xL. In either resting or CD40L-activated B cells, the NF-kappaB transcription factors RelB and p50 are specifically activated, suggesting that they may mediate BLyS signals for B cell survival. Together, these results provide direct evidence for BLyS enhancement of both T cell-independent and T cell-dependent humoral immune responses, and imply a role for BLyS in the conservation of the B cell repertoire. The ability of BLyS to increase B cell survival indiscriminately, at either a resting or activated state, and to cooperate with CD40L, further suggests that attenuation of apoptosis underlies BLyS enhancement of polyclonal autoimmunity as well as the physiologic humoral immune response.
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PMID:Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response. 1101 37


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