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)

Kainic acid induces excitotoxicity and nerve cell degeneration in vulnerable regions of rat brain, most markedly in hippocampus and amygdala. Part of the cell death following kainic acid is apoptotic as shown by caspase 3 activation and chromatin condensation. Here we have studied the regulation of pro- and anti-apoptotic proteins belonging to the Bcl-2 family in rat hippocampus and amygdala by kainic acid in relationship to ensuing neuronal death. The pro-apoptotic protein Bax was up-regulated in hippocampus 6 h after kainic acid administration. The increase in Bax was followed by the appearance of TdT-mediated dUTP nick end labelling-positive cells which were prominent at 24 h. Immunohistochemistry for active Bax revealed a punctuated labelling of neurons in the CA3 and hilar regions of hippocampus as well as in amygdala. Double staining for NeuN, a marker for nerve cells, and TdT-mediated dUTP nick end labelling showed that mainly neurons undergo degeneration after kainic acid treatment. In contrast to Bax, the pro-apoptotic BH3-only Bcl-2 proteins Bim and Harakiri/DP5 were down-regulated by kainic acid. This was also observed for the anti-apoptotic proteins Bcl-x and Bcl-w. Immunoreactive Bcl-2 was up-regulated in hippocampus after kainic acid together with an increase in the phosphorylation of serine-87 in Bcl-2, suggesting a post-transcriptional modification of the protein. This was confirmed using immunoprecipitation of total Bcl-2 from hippocampus and amygdala which revealed an increase in serine-87 phospho-Bcl-2 after kainic acid. Inhibition of the c-jun N-terminal protein kinase pathway reduced both serine-87 phosphorylation and cell death after kainic acid. This indicates an important role of Bcl-2 phosphorylation in controlling neuronal death after kainic acid. In contrast to the situation in trophic factor-deprived neurons, no up-regulation of Bim or Harakiri/DP5 proteins occurred after kainic acid, suggesting alternative pathways for regulation of cell death in excitotoxicity. The results indicate that not only the relative levels of Bcl-2 family proteins but also conformation changes and post-translational modifications contribute to neuronal death following kainic acid.
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PMID:Increase in Bcl-2 phosphorylation and reduced levels of BH3-only Bcl-2 family proteins in kainic acid-mediated neuronal death in the rat brain. 1295 12

Pro-apoptotic functions of the BH3-only protein BAD are negatively regulated by survival signal-mediated phosphorylation at several serine residues. Recently, we found that the mutant BAD (BADD119G) with an amino acid substitution of Asp (Asp119 to Gly) within the BH3 domain displays strong pro-apoptotic activity in serum-starved COS-7 cells, although it cannot interact with Bcl-2. Here, we demonstrate that the BADD119G loses phosphorylation-mediated negative regulation. Importantly, pro-apoptotic activity of wild-type BAD (BADwt) was strongly suppressed by co-transfection with constitutively active Akt (CA-Akt) cDNA, whereas that of BADD119G was not. In these transfectants, BADD119G phosphorylation was barely detectable at serine residues (S75 and S99), although BADwt phosphorylation was clearly increased by CA-Akt. In addition, various external stimuli UV, TPA and forskolin could not phosphorylate BADD119G neither at S75, S99 nor S118 in COS-7 cells. However, in vitro kinase assay revealed that catalytic protein kinase A (PKA) strongly phosphorylated both BADs at S75 and S118, excluding the possibility that the target sequence of PKA was disrupted by mutation at S119. Furthermore, as a result of disrupted phosphorylation, BADD119G could not physically interact with 14-3-3. Taken together, disruption of phosphorylation-mediated negative regulation may explain, at least in part, the strong pro-apoptotic functions of BADD119G, and suggest a role for the BH3 domain in phosphorylation events.
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PMID:Mutation of BAD within the BH3 domain impairs its phosphorylation-mediated regulation. 1296 20

Proteolysis is central to the systematic cellular degradation that occurs during apoptosis. Predominantly, caspases have been studied in this regard. However, increasing evidence suggests that certain serine proteases may also play a significant role in apoptosis. Not only are these serine proteases involved in apoptosis signalling pathways independently, but they may also interact with more classical mediators of apoptosis such as the caspases or Bcl-2 family proteins. Isolation of apoptosis-associated serine proteases and the use of specific inhibitors have helped to shed light on potential pathways in which they are involved. Despite the recent developments in the field, knowledge regarding the role of serine proteases in apoptosis remains limited, but it is clear that investigations are gathering momentum and such studies may herald a new and exciting departure in apoptosis research.
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PMID:In the cut and thrust of apoptosis, serine proteases come of age. 1455 23

Bim is a proapoptotic member of the Bcl-2 family that shares only the BH3 domain with this family. Three Bim proteins Bim-EL, Bim-L and Bim-S are synthesized from the same transcript. We report here that Bim-EL when phosphorylated by Erk1/2 is rapidly degraded via the proteasome pathway. Using different cellular models we evidence that serine 69 is both necessary and sufficient for Erk1/2-mediated phosphorylation and degradation of Bim-EL. In K562 cells, Phorbol 12-myristate 13-acetate activates Erk1/2 and consequently increases Bim-EL phosphorylation and degradation by the proteasome, resulting in cell survival, while the Bcr-Abl inhibitor imatinib abrogates Bim-EL phosphorylation and degradation and induces caspase activation and apoptosis. We also show that Bim-EL(S69G) promotes apoptosis more efficiently than Bim-EL-WT in K562 cells. Altogether, our findings demonstrate that phosphorylation of Bim-EL by Erk1/2 on serine 69 selectively leads to its proteasomal degradation and therefore represents a new and important mechanism of Bim regulation.
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PMID:Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function. 1455 91

The reversible phosphorylation of proteins controlled by protein kinases and protein phosphatases is a major mechanism that regulates a wide variety of cellular processes. In contrast to C. elegans, recent studies in mammalian cells have highlighted a major role of serine/threonine protein phosphorylation in apoptosis. To illustrate the importance of dephosphorylation processes in apoptosis, this review will focus on recent studies suggesting that the interaction of the serine/threonine protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) with certain regulators of the Bcl-2 family is critically involved in the control of apoptosis.
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PMID:Serine/threonine protein phosphatases PP1 and PP2A are key players in apoptosis. 1458 37

Signaling through the B cell antigen receptor (BCR) is a key determinant in the regulation of B cell physiology. Depending on additional factors, such as microenvironment and developmental stage, ligation of the BCR can trigger B lymphocyte activation, proliferation, or apoptosis. The regulatory mechanisms determining B cell apoptosis and survival are not completely known. Using the murine B lymphoma cell line WEHI-231 as a model system, we investigated the role of Bad phosphorylation, a pro-apoptotic member of the Bcl-2 family, in anti-IgM mediated apoptosis. For apoptotic analysis we focused in particular on the mitochondrial potential (deltapsi(m)) collapse which has been reported as a rate-limiting step in the BCR-induced cell death of immature B lymphocytes. Bad phosphorylation at serine 112, 136 and 155 was found in WEHI-231 cell control cultures and its hypophosphorylation on the three sites correlated with the appearance of apoptosis when cross-linking surface IgM. Furthermore, treatment of cells with specific PK inhibitors known to be involved in serine phosphorylation of Bad (LY294002 for PI3K and H-89 for PKA) mimiced or enhanced BCR-induced cell death. These results strongly suggest that regulation of Bad phosphorylation plays an active role in mediating anti-IgM-induced apoptosis of immature B cells.
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PMID:Changes in bad phosphorylation are correlated with BCR-induced apoptosis of WEHI-231 immature B cells. 1458 39

Oxidative stress, produced as a consequence of normal metabolism or induced by extraneous stimuli, has been proved to be a mediator of cell death. The inherent antioxidant defense system and exogenous antioxidants can help the body to combat this oxidative stress-induced cell death. In this study, we explored the antiapoptotic potential of gallic acid, a dietary phenolic having antioxidative and anticarcinogenic properties, in normal human peripheral blood lymphocytes (PBLs). Incubation of PBLs with 100 microM H2O2 for 1.5-2.0 h induced phosphatidyl serine externalisation, lipid peroxidation and high molecular weight DNA fragmentation. Pretreatment of lymphocytes with gallic acid for 18 h could effectively inhibit lipid peroxidation and apoptosis induced by oxidative stress. Treatment of PBLs with gallic acid failed to induce any change in the expression of Bcl-2, an antiapoptotic protein. It seems that the protection provided by gallic acid was due to its direct action in the scavenging of free radicals as it was found to be a stronger antiradical than trolox, a water- soluble analogue of vitamin E.
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PMID:Gallic acid, an antioxidant, exhibits antiapoptotic potential in normal human lymphocytes: A Bcl-2 independent mechanism. 1459 7

Bik was initially identified as a BH3-domain-only protein that interacts with E1B 19K. Although systemically administered wild-type Bik significantly inhibited tumor growth and metastasis in an orthotopic nude mouse model, the proapoptotic potency of Bik can be modulated by posttranslational phosphorylation. Here, we found that Bik mutants, in which threonine 33 and/or serine 35 were changed to aspartic acid to mimic the phosphorylation at these two residues, enhanced their binding affinity with the antiapoptotic proteins Bcl-X(L) and Bcl-2 and were more potent than wild-type Bik in inducing apoptosis and inhibiting cell proliferation in various human cancer cells. Bik mutants also suppressed tumorigenicity and tumor-taking rate in a mouse ex vivo model. Moreover, Bik mutant-liposome complexes inhibited tumor growth and prolonged life span more effectively than the wild-type Bik-liposome complex in an in vivo orthotopic animal model. Thus, our results demonstrate that Bik mutant genes, more potent than wild-type Bik, induce cell death and suggest that their inhibition on the growth of various cancers should be explored further.
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PMID:Enhancement of Bik antitumor effect by Bik mutants. 1463 80

We have previously demonstrated that Bcl-2 overexpression in human breast carcinoma and melanoma cells synergizes with hypoxia to increase angiogenesis through up-regulation of vascular endothelial growth factor. In this work we demonstrated, for the first time, that Bcl-2 overexpression in cancer cells exposed to hypoxia modulates urokinase plasminogen activator receptor (uPAR) expression through Sp1 transcription factor and that the extracellular signal-regulated kinase (ERK) pathway plays a role in Sp1 transcriptional activity. In particular, an increase in uPAR protein and mRNA expression was found in melanoma bcl-2 transfectants grown under hypoxia when compared with control cells, and a decrease of uPAR protein expression was induced by treatment of cells with specific bcl-2 antisense oligonucleotides. Up-regulation of uPAR expression was accompanied by increased Sp1 protein expression, stability, serine phosphorylation, and DNA binding activity. Treatment of cells with mitramycin A, an inhibitor of Sp1 activity, confirmed the role of Sp1 transcriptional activity in uPAR induction by Bcl-2. The contribution of the ERK pathway in Sp1-increased transcriptional activity was demonstrated by the use of chemical inhibition. In fact, ERK kinase activation was induced in Bcl-2-overexpressing cells exposed to hypoxia, and the ERK kinase inhibitor UO126 was able to down-regulate Sp1 phosphorylation and DNA binding activity. Using a human breast carcinoma line, we obtained data supporting our findings with melanoma cells and identified a link between the induction of Sp1 and uPAR expression as a common bcl-2-controlled phenomenon in human tumors. In conclusion, our results strongly indicate that up-regulation of uPAR expression by Bcl-2 in hypoxia is modulated by Sp1 DNA binding activity through the ERK signaling pathway.
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PMID:bcl-2 induction of urokinase plasminogen activator receptor expression in human cancer cells through Sp1 activation: involvement of ERK1/ERK2 activity. 1466 Jun 75

The oncogene Bcl-2 is upregulated frequently in prostate tumors following androgen ablation therapy, and Bcl-2 overexpression may contribute to the androgen-refractory relapse of the disease. However, the molecular mechanism underlying androgenic regulation of Bcl-2 in prostate cancer cells is understood poorly. In this study, we demonstrated that no androgen response element (ARE) was identified in the androgen-regulated region of the P1 promoter of Bcl-2 gene, whereas, we provided evidence that the androgenic effect is mediated by E2F1 protein through a putative E2F-binding site in the promoter. We further demonstrated that retinoblastoma (RB) protein plays a critical role in androgen regulation of Bcl-2. The phosphorylation levels of RB at serine residues 780 and 795 were decreased in LNCaP cells treated with androgens. Ectopic expression of a constitutively active form of RB inhibited expression of Bcl-2. Knockdown of endogenous RB protein by an Rb small inference RNA (siRNA) induced an increase in Bcl-2 levels. Most importantly, the effect of androgens on Bcl-2 was abolished completely by specific inhibition of RB function with a mutated E1A. Finally, androgen treatment of LNCaP cells upregulated specifically levels of the cyclin-dependent kinase inhibitors (CDKIs) p15INK4B and p27KIP1. Ectopic expression of p15INK4B and/or p27KIP1 inhibited Bcl-2 expression. Knockdown of endogenous p15INK4B or p27KIP1 protein with a pool of siRNAs diminished androgen-induced downregulation of Bcl-2 expression. Therefore, our data indicate that androgens suppress Bcl-2 expression through negatively modulating activities of the E2F site in the Bcl-2 promoter by activating the CDKI-RB axis.
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PMID:Androgens repress Bcl-2 expression via activation of the retinoblastoma (RB) protein in prostate cancer cells. 1467 36


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