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)

The proliferation and survival of a B cell population is necessarily tightly controlled to prevent the arisal of malignancy or autoimmunity. The expansion or elimination of a B cell clone is determined through a complex interaction of the tumour necrosis factor receptor/nerve growth factor receptor family members CD40 and Fas, which are expressed on the B cell surface, with their respective physiological ligands (CD40L and FasL) expressed on the surface of CD4+ T cells. The regulation of B cell growth by signals transduced through CD40 and Fas contributes to the maintenance of peripheral tolerance and likely takes place and in the germinal centres (GC) of secondary lymphoid tissues. In this study, we investigate the relationship between the expression of Fas and B cell survival following engagement of CD40 and Fas in the Epstein-Barr virus-genome-negative Ramos-Burkitt lymphoma (Ramos-BL) B cell line model of GC B lymphocyte selection during maturation of the humoral immune response. We now present evidence that Ramos-BL B cells constitutively express both Fas and FasL on their surface and that expression of Fas, but not FasL, is enhanced following ligation of CD40. Coligation of CD40 and Fas, triggers for growth inhibition, activation of the interleukin-1 beta-converting enzyme, now caspase, family member CPP32 (caspase-3) but not Ich-1L (caspase-2), cleavage of its death substrate poly(ADP-ribose) polymerase, and apoptosis from the G1 phase of cell cycle; engagement of Fas alone fails to trigger for growth inhibition and apoptosis but enhances AgR-mediated cellular death. This CD40-potentiated Fas-triggered growth inhibition and apoptosis occurs in the presence of CD40-induced expression of the anti-apoptotic proteins Bcl-xL and Bcl-2. Taken together, these data indicate that ligation of CD40 facilitates efficient coupling of Fas to the caspase-mediated pathway of apoptosis.
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PMID:Ligation of CD40 potentiates Fas-mediated activation of the cysteine protease CPP32, cleavage of its death substrate PARP, and apoptosis in Ramos-Burkitt lymphoma B cells. 939 1

The barrier function of mitochondrial membranes is perturbed early during the apoptotic process. Here we show that the mitochondria contain a caspase-like enzymatic activity cleaving the caspase substrate Z-VAD.afc, in addition to three biological activities previously suggested to participate in the apoptotic process: (a) cytochrome c; (b) an apoptosis-inducing factor (AIF) which causes isolated nuclei to undergo apoptosis in vitro; and (c) a DNAse activity. All of these factors, which are biochemically distinct, are released upon opening of the permeability transition (PT) pore in a coordinate, Bcl-2-inhibitable fashion. Caspase inhibitors fully neutralize the Z-VAD.afc-cleaving activity, have a limited effect on the AIF activity, and have no effect at all on the DNase activities. Purification of proteins reacting with the biotinylated caspase substrate Z-VAD, immunodetection, and immunodepletion experiments reveal the presence of procaspase-2 and -9 in mitochondria. Upon induction of PT pore opening, these procaspases are released from purified mitochondria and become activated. Similarly, upon induction of apoptosis, both procaspases redistribute from the mitochondrion to the cytosol and are processed to generate enzymatically active caspases. This redistribution is inhibited by Bcl-2. Recombinant caspase-2 and -9 suffice to provoke full-blown apoptosis upon microinjection into cells. Altogether, these data suggest that caspase-2 and -9 zymogens are essentially localized in mitochondria and that the disruption of the outer mitochondrial membrane occurring early during apoptosis may be critical for their subcellular redistribution and activation.
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PMID:Mitochondrial release of caspase-2 and -9 during the apoptotic process. 989 20

Apoptosis is accompanied by the activation of a number of apoptotic proteases (caspases) which selectively cleave specific cellular substrates. Caspases themselves are zymogens which are activated by proteolysis. It is widely believed that 'initiator' caspases are recruited to and activated within apoptotic signalling complexes, and then cleave and activate downstream 'effector' caspases. While activation of the effector caspase, caspase-3, has indeed been observed as distal to activation of several different initiator caspases, evidence for a further downstream proteolytic cascade is limited. In particular, there is little evidence that cellular levels of caspase-3 that are activated via one pathway are sufficient to cleave and activate other initiator caspases. To address this issue, the ability of caspase-3, activated upon addition to cytosolic extracts of cytochrome c, to cause cleavage of caspase-2 was investigated. It was demonstrated that cleavage of caspase-2 follows, and is dependent upon, activation of caspase-3. Moreover, the activation of both caspases was inhibited by Bcl-2. Together, these data indicate that Bcl-2 can protect cells from apoptosis by acting at a point downstream from release of mitochondrial cytochrome c, thereby preventing a caspase-3 dependent proteolytic cascade.
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PMID:Bcl-2 regulates a caspase-3/caspase-2 apoptotic cascade in cytosolic extracts. 1008 32

The effects of Bcl-2 overexpression on several of its multifunctional characteristics, which include anti-apoptotic properties, impeding of cell proliferation, and telomerase activity, were examined in four Jurkat T cell clones overexpressing different levels of Bcl-2. When treated with anti-Fas or staurosporine, only three of the four clones showed resistance to apoptosis that correlated with the level of Bcl-2 expression. Surprisingly, the clone having no anti-apoptotic characteristic expressed the highest level of Bcl-2. When all the clones were treated with anti-Fas the processing of caspase-2, -3, and -7 but not -8 was inhibited in the resistant clones to a similar extent by the differential overexpression of Bcl-2. However, with staurosporine treatment the processing of all the caspases examined was inhibited to a similar degree by the different levels of Bcl-2 expression in the resistant clones. These results suggest that Bcl-2 blocked Fas-mediated cell death by acting downstream of caspase-8, which is in contrast to staurosporine-induced apoptosis where Bcl-2 is acting upstream of caspase-8. When the anti-proliferative effect of Bcl-2 was examined, a direct correlation between a decrease in cell proliferation and the level of Bcl-2 overexpressed in the clones was observed. The clone overexpressing the greatest amount of Bcl-2 protein, which had no resistance to apoptosis, had the slowest proliferative rate. This suggests that the anti-apoptotic effect of Bcl-2 can be separated from its anti-proliferative effect. The possible effect of overexpression of Bcl-2 on telomerase activity, which is known to control the proliferative capacity of normal cells and cellular senescence, was also determined. Our results suggest that Bcl-2 had no effect on telomerase activity or telomere length in the clones. In summary, our results further suggest that some properties of Bcl-2, such as anti-apoptotic and inhibition of cell proliferation, are individual features of a multifaceted protein.
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PMID:Effects of differential overexpression of Bcl-2 on apoptosis, proliferation, and telomerase activity in Jurkat T cells. 1043 83

The MDM2 oncoprotein has been shown to inhibit p53-mediated growth arrest and apoptosis. It also confers growth advantage to different cell lines in the absence of p53. Recently, the ability of MDM2 to arrest the cell cycle of normal human fibroblasts has also been described. We report a novel function for this protein, showing that overexpression of MDM2 promotes apoptosis in p53-deficient, human medullary thyroid carcinoma cells. These cells, devoid of endogenous MDM2 protein, exhibited a significant growth retardation after stable transfection with mdm2. Cell cycle distribution of MDM2 transfectants [medullary thyroid tumor (MTT)-mdm2] revealed a fraction of the cell population in a hypodiploid status, suggesting that MDM2 is sufficient to promote apoptosis. This circumstance is further demonstrated by annexin V labeling. MDM2-induced apoptosis is partially reverted by transient transfection with p53 and p19ARF. Both MTT and MTT-mdm2 cells were tumorigenic when injected into nude mice. However, the percentage ofapoptotic nuclei in tumor sections derived from MDM2-expressing cells was significantly higher relative to that in the parental cell line. MDM2-mediated programmed cell death is at least mediated by a down-regulation of the antiapoptotic protein Bcl-2. Protein levels of caspase-2, which are undetectable in the parental cell line, appear clearly elevated in MTT-mdm2 cells. Caspase-3 activation does not participate in MDM2-induced apoptosis, as determined by protein levels or poly(ADP-ribose) polymerase fragmentation. The results observed in this medullary carcinoma cell line show for the first time that the product of the mdm2 oncogene mediates cell death by apoptosis in p53-deficient tumor cells.
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PMID:The MDM2 oncoprotein promotes apoptosis in p53-deficient human medullary thyroid carcinoma cells. 1061 65

Neutrophils possess a very short lifespan, dying by apoptosis. HL-60 cells undergo apoptosis after neutrophil differentiation with dimethyl sulfoxide (DMSO). We have found that the onset of apoptosis in neutrophil-differentiating HL-60 cells correlates with the achievement of an apoptosis-related gene expression pattern similar to that of peripheral blood mature neutrophils. Using reverse transcriptase-polymerase chain reaction, cloning, and sequencing techniques, we have found that HL-60 cells express bak, bik, bax, bad, bcl-2, bcl-xL, bcl-w, bfl-1, fas, and caspases 1-4 and 7-10. After DMSO treatment, bak, bcl-w, bfl-1, fas, and caspases 1 and 9 were up-regulated, whereas bik, bcl-2, and caspases 2, 3, and 10 were down-regulated at different degrees, achieving mRNA expression levels that correlated with those detected in peripheral blood neutrophils. Caspase-2 mRNA and protein expression was drastically reduced after HL-60 cell differentiation, being absent in both HL-60-differentiated neutrophils and mature neutrophils, whereas caspase-3 and -10 mRNA and protein expression were diminished upon HL-60 cell differentiation until achieving the respective levels found in mature neutrophils. Bak and bfl-1 mRNA levels were largely increased during DMSO-induced differentiation of HL-60 cells, and these genes were the bcl-2 family members that were expressed most abundantly in mature neutrophils. Bcl-2 overexpression or caspase inhibition prevented differentiation-induced apoptosis in HL-60 cells, but not their differentiation capability. Neutrophil spontaneous apoptosis was also blocked by the caspase inhibitor z-Asp-2,6-dichlorobenzoyloxymethylketone. Peripheral blood neutrophils expressed bak, bad, bcl-w, bfl-1, fas, and caspases 1, 3, 4, and 7-10, but hardly expressed bcl-2, bcl-xL, bik, bax, and caspase-2. These results suggest that the above gene expression changes in neutrophil-differentiating HL-60 cells may play a role in the acquisition of the neutrophil apoptotic features.
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PMID:Expression of genes involved in initiation, regulation, and execution of apoptosis in human neutrophils and during neutrophil differentiation of HL-60 cells. 1081 Oct 13

A RIP-like protein, RIP3, has recently been reported that contains an N-terminal kinase domain and a novel C-terminal domain that promotes apoptosis. These experiments further characterize RIP3-mediated apoptosis and NF-kappaB activation. Northern blots indicate that rip3 mRNA displays a restricted pattern of expression including regions of the adult central nervous system. The rip3 gene was localized by fluorescent in situ hybridization to human chromosome 14q11.2, a region frequently altered in several types of neoplasia. RIP3-mediated apoptosis was inhibited by Bcl-2, Bcl-x(L), dominant-negative FADD, as well as the general caspase inhibitor Z-VAD. Further dissection of caspase involvement in RIP3-induced apoptosis indicated inhibition by the more specific inhibitors Z-DEVD (caspase-3, -6, -7, -8, and -10) and Z-VDVAD (caspase-2). However, caspase-1, -6, -8 and -9 inhibitors had little or no effect on RIP3-mediated apoptosis. Mutational analysis of RIP3 revealed that the C-terminus of RIP3 contributed to its apoptotic activity. This region is similar, but distinct, to the death domain found in many pro-apoptotic receptors and adapter proteins, including FAS, FADD, TNFR1, and RIP. Furthermore, point mutations of RIP3 at amino acids conserved among death domains, abrogated its apoptotic activity. RIP3 was localized by immunofluorescence to the mitochondrion and may play a key role in the mitochondrial disruptions often associated with apoptosis.
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PMID:The RIP-like kinase, RIP3, induces apoptosis and NF-kappaB nuclear translocation and localizes to mitochondria. 1081 27

An increasing number of proteins are implicated in apoptosis and several of them have been shown to be altered in Alzheimer's disease (AD) brain. Because of this apoptosis is thought to be the underlying mechanism of neuronal cell loss in AD. To further substantiate this hypothesis we investigated the expression of a recently identified apoptosis related proteins and other apoptosis regulators in frontal cortex and cerebellum of AD by Western blot and enzyme-linked immunsorbent assay technique. Quantitative analysis revealed unaltered levels of Bax and RAIDD (Receptor interacting protein associated ICH-1 (caspase-2)/CED-3 (Caenorhabditis elegans death protease-3)-homologous protein with death domain) in both regions. ZIP (Zipper interacting protein) kinase, Bim/BOD (Bcl-2 interacting mediator of cell death/Bcl-2 related ovarian death gene) and p21 were significantly increased only in AD frontal cortex (P < 0.05, in all cases). Cerebellar Bcl-2 levels were significantly increased in AD (P < 0.01) while in AD frontal cortex, although the levels tended to increase did not reach significance level. The results indicate that apoptosis indeed account for the neuronal loss in AD. However, it does not seem to involve Bax and RAIDD.
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PMID:Expression of apoptosis related proteins in brains of patients with Alzheimer's disease. 1131 97

Garcinol, a polyisoprenylated benzophenone, was purified from Garcinia indica fruit rind. The effects of garcinol and curcumin on cell viability in human leukemia HL-60 cells were investigated. Garcinol and curcumin displayed strong growth inhibitory effects against human leukemia HL-60 cells, with estimated IC(50) values of 9.42 and 19.5 microM, respectively. Garcinol was able to induce apoptosis in a concentration- and time-dependent manner; however, curcumin was less effective. Treatment with garcinol caused induction of caspase-3/CPP32 activity in a dose- and time-dependent manner, but not caspase-1 activity, and induced the degradation of poly(ADP-ribose) polymerase (PARP). Pretreatment with caspase-3 inhibitor inhibited garcinol-induced DNA fragmentation. Treatment with garcinol (20 microM) caused a rapid loss of mitochondrial transmembrane potential, release of mitochondrial cytochrome c into cytosol, and subsequent induction of procaspase-9 processing. The cleavage of D4-GDI, an abundant hematopoietic cell GDP dissociation inhibitor for the Ras-related Rho family GTPases, occurred simultaneously with the activation of caspase-3 but preceded DNA fragmentation and the morphological changes associated with apoptotic cell death. Of these, Bcl-2, Bad, and Bax were studied. The level of expression of Bcl-2 slightly decreased, while the levels of Bad and Bax were dramatically increased in cells treated with garcinol. These results indicate that garcinol allows caspase-activated deoxyribonuclease to enter the nucleus and degrade chromosomal DNA and induces DFF-45 (DNA fragmentation factor) degradation. It is suggested that garcinol-induced apoptosis is triggered by the release of cytochrome c into the cytosol, procaspase-9 processing, activation of caspase-3 and caspase-2, degradation of PARP, and DNA fragmentation caused by the caspase-activated deoxyribonuclease through the digestion of DFF-45. The induction of apoptosis by garcinol may provide a pivotal mechanism for its cancer chemopreventive action.
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PMID:Induction of apoptosis by garcinol and curcumin through cytochrome c release and activation of caspases in human leukemia HL-60 cells. 1131 81

We investigated the mechanism by which 4-hydroxynonenal (HNE), a major aldehydic product of lipid peroxidation, induces apoptosis in tumor cells. Treatment of human colorectal carcinoma (RKO) cells with HNE-induced poly-ADP-ribose-polymerase (PARP) cleavage and DNA fragmentation in a dose- and time-dependent manner. The induction of PARP cleavage and DNA fragmentation paralleled caspase-2, -3, -8, and -9 activation. Pretreatment of cells with an inhibitor of caspase-3, z-DEVD-fmk, or a broad spectrum caspase inhibitor, z-VAD-fmk, abolished caspase activation and subsequent PARP cleavage. Constitutive expression of high levels of Bcl-2 protected cells from HNE-mediated apoptosis. In addition, Bcl-2 overexpression inhibited cytochrome c release from mitochondria and subsequent caspase-2, -3, and -9 activation. These findings demonstrate that HNE triggers apoptotic cell death through a mitochondrion-dependent pathway involving cytochrome c release and caspase activation. Bcl-2 overexpression protected cells from HNE-induced apoptosis through inhibition of cytochrome c release.
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PMID:4-hydroxynonenal induces apoptosis via caspase-3 activation and cytochrome c release. 1151 Nov 83

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