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)

The role of intracellular acidification in the execution phase of apoptosis is not well understood. Here we examine the effect of Bcl-2 over-expression on intracellular acidification occurring during apoptosis. We found, that in CEM cells, neither DEX nor VP16-induced apoptosis lead to a significant change in intracellular pH (pHi). Furthermore, we found that shifting pHi away from physiological values was unable to induce chromatin condensation or poly(ADP-ribose) polymerase (PARP) cleavage in the presence of Bcl-2 over-expression. However, it was found that maximum chromatin condensation and PARP cleavage occurred at near physiological pHi values. Taken together these data suggest that intracellular acidification does not trigger the effector phase of CEM apoptosis.
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PMID:Cytoplasmic acidification is not an effector mechanism of VP16 or DEX-induced apoptosis in CEM T leukaemia cells. 1031 67

The proto-oncogene product Bcl-2 protects a wide variety of cell types from apoptosis via a hitherto unknown mechanism. Bcl-2 has been shown to function upstream of the death proteases (caspases) in some, but not all, occurrences of apoptotic cell death. Using the myeloid leukemic cell line P39 we report the chemotherapy-induced caspase-dependent cleavage of endogenous Bcl-2. Etoposide treatment of these cells triggered a time-dependent activation of type II and type III caspases and cleavage of Bcl-2 yielding a 23 kDa cleavage fragment. The emergence of this cleavage product was blocked by the general caspase inhibitor zVAD-fmk, as well as the type III caspase inhibitor IETD-fmk and the caspase-9-selective inhibitor LEHD-fmk, while the type II caspase inhibitor DEVD-fmk proved considerably less efficient. Bcl-2 cleavage preceded cleavage of the known caspase-3 substrate, poly(ADP-ribose) polymerase (PARP), as well as that of the caspase-6 substrate, lamin B, indicating that Bcl-2 cleavage is a relatively early event in the apoptosis cascade in this experimental model. While evidence for cleavage of Bcl-2 in several subcellular compartments of etoposide-treated cells was obtained, this cleavage was detected predominantly in the mitochondrial fraction, thus providing further support for the central role of mitochondria in apoptosis. Caspase-mediated cleavage following etoposide treatment of these myeloid leukemic cells may represent a means for the attenuation of Bcl-2 function upon apoptosis induction.
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PMID:Cleavage of Bcl-2 is an early event in chemotherapy-induced apoptosis of human myeloid leukemia cells. 1037 76

The colonic epithelial cells near the top of the crypt and in the lumen have been shown to undergo apoptosis. Since butyric acid is the major short-chain fatty acid produced by fermentation of dietary fiber in the large bowel, it has been proposed that it could act as an important regulator of apoptosis in colorectal cancer. Here we report that in cells treated with butyric acid, the cleavage of DNA-PKcs was paralleled or preceded by the induction of activation of caspase-3, and these events were inhibited by Bcl-2 overexpression. We also demonstrated the redistribution of activated caspase-3 to the nuclear compartment where it locally cleaves DNA-PKcs and poly(ADP-ribose) polymerase, and cleaved fragments were released in the cytosolic compartment. The observed activation of caspase-3 and nuclear cleavage of its substrates and their subsequent release into the cytosol were inhibited by a specific caspase-3 inhibitor, the tetrapeptide DEVD-CHO. These findings suggest that relocalization of activated caspase-3 to the nucleus may constitute an important apoptotic signal during butyric acid-induction of apoptosis human colorectal cancer cells.
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PMID:Redistribution of activated caspase-3 to the nucleus during butyric acid-induced apoptosis. 1040 41

Treatment with the photosensitizer benzoporphyrin derivative monoacid ring A (BPD-MA, verteporfin) followed by irradiation with visible light induces apoptosis in human acute myelogenous leukaemia HL-60 cells. Photoactivation of BPD-MA induces procaspase 3 (CPP32/Yama/apopain) and procaspase 6 (Mch2) cleavage into their proteolytically active subunits in these cells. The Bcl-2 proto-oncogene product has been shown to protect cells from a number of proapoptotic stimuli. In the present study, the influence of Bcl-2 overexpression on cellular resistance to photoactivation of BPD-MA was studied. Overexpression of Bcl-2 in HL-60 cells prevented apoptosis-related events including caspase 3 and 6 activation, poly(ADP-ribose) polymerase cleavage and the formation of hypodiploid DNA produced by BPD-MA (0-200 ng ml(-1)) and light. However, Bcl-2 overexpression was less effective at preventing cell death that occurred after photoactivation at high levels (50-100 ng ml(-1)) compared with lower doses (10-25 ng ml(-1)) of BPD-MA. These results indicate that caspase 3 and 6 activation and their regulation by Bcl-2 may play important roles in photodynamic therapy (PDT)-induced cell killing.
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PMID:Bcl-2 overexpression blocks caspase activation and downstream apoptotic events instigated by photodynamic therapy. 1040 99

Breast cancer is the most common cancer and second leading cause of cancer related deaths in women in the United States. Genistein is a protein tyrosine kinase inhibitor and prominent isoflavonoid in soy products and has been proposed as the agent responsible for lowering the rate of breast cancer in Asian women. We have previously shown that genistein inhibits the growth of MDA-MB-231 breast cancer cells, regulates the expression of apoptosis-related genes, and induces apoptosis through a p53-independent pathway. In this study, we investigated these effects of genistein in the breast cancer cell line MDA-MB-435 and 435.eB cells that were established by transfecting c-erbB-2 cDNA into MDA-MB-435. We also investigated the effect of genistein on matrix metalloproteinase (MMP) secretion previously shown to be effected by erbB-2 transfection. Genistein was found to inhibit MDA-MB-435 and 435.eB cell growth. Induction of apoptosis was also observed in these cell lines when treated with genistein, as measured by DNA laddering, poly(ADP-ribose) polymerase (PARP) cleavage, and flow cytometric analysis. We also found an up-regulation of Bax and p21WAF1 expression and down-regulation of Bcl-2 and c-erbB-2 in genistein-treated cells. Gelatin zymography showed that genistein inhibits the secretion of MMP in the breast cancer cells. From these results, we conclude that genistein inhibits the growth of MDA-MB-435 breast cancer cells, induces apoptosis, regulates the expression of genes, and may inhibit invasion and metastasis of breast cancer cells. These findings suggest that genistein may be a potentially effective chemopreventive or therapeutic agent against breast cancer.
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PMID:Induction of apoptosis and inhibition of c-erbB-2 in MDA-MB-435 cells by genistein. 1042 35

Bcl-2 family proteins and interleukin-1-beta converting enzyme/Caenorhabditis elegans cell death gene-3 (ICE/CED-3) family proteases (caspases) represent the basic regulators of apoptosis. However, the precise mechanism by which they interact is unclear. In this study, we found that gamma-radiation-induced apoptosis of leukemia cells was associated with activation of multiple caspases and bax up-regulation. Membrane changes and caspase activities were suppressed by specific caspase inhibitors. Similarly, the serine protease inhibitors z-Ala-Ala-Asp-cmk (AAD) and tosyl-lysine chloromethyl ketone (TLCK) also prevented caspase activation and poly(ADP-ribose) polymerase cleavage in vivo but had no effect on caspase activity in vitro. TLCK also prevented bax up-regulation as a result of its inhibitory effect on p53 function. Inhibitors of caspases and serine proteases partially prevented cell death, suggesting a caspase involvement in Bax-mediated cell death. We propose an ordering of signaling events in Bax-mediated cell death, including steps upstream and downstream of p53 and bax up-regulation.
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PMID:Ionizing radiation-induced, Bax-mediated cell death is dependent on activation of cysteine and serine proteases. 1043 17

We have previously shown that malignant B cells from non-Hodgkin's lymphomas (NHL) are resistant to Fas-mediated apoptosis. To determine the mechanisms underlying this resistance, we analysed by Western blotting the expression of several apoptotic regulators, caspase 3, caspase 8, FADD and poly(ADP-ribose) polymerase (PARP) in fresh lymphoma cells, isolated from 16 B-NHL biopsy samples of different histological subtypes, and displaying variable levels of Fas expression. The profiles of expression of these apoptotic regulators were monitored in cell lysates at different times following Fas with or without CD40 stimulation. Expression of FADD and of the uncleaved forms of PARP, caspase 3 and caspase 8 were detected in all untreated NHL samples. Low levels of PARP cleavage were noted in three untreated samples. Fas stimulation alone induced neither significant apoptosis nor significant changes in the expression profiles of FADD, caspases 3 and 8 and PARP in the 16 samples, except for variations in FADD and caspase 8 expression levels in a minority of samples. Fas/CD40 co-stimulation induced apoptosis and cleavage of caspase 3, caspase 8 and PARP in the five NHLs tested; expression of FADD was not modified. Our results showed (1) that induction of apoptosis in B-NHLs by Fas/CD40 co-stimulation used the same caspase executioner machinery as the normal Fas pathway, and (2) that NHL cells which resisted Fas-mediated apoptosis displayed no defect in either expression or functionality of caspases 3 and 8, nor in FADD expression. The dysfunction underlying NHL resistance to apoptosis must therefore lie upstream of caspase 8, or could alternatively be influenced by anti-apoptotic regulators of the Bcl-2 family.
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PMID:FADD expression and caspase activation in B-cell lymphomas resistant to Fas-mediated apoptosis. 1046 53

Time-dependent ladder-type DNA fragmentation and morphological alterations consistent with apoptosis were observed among A253 human head and neck squamous cell carcinoma (HNSCC) cells in nude mice from 15 to 18 days after transplantation, without any drug treatment. No evidence of ladder-type DNA fragmentation was detected in A253 cells in vitro or in normal nude mouse tissues (skin and muscle). Our aim was to explore molecular factors associated with such spontaneous apoptosis. Bcl-2 protein expression decreased, while bax protein expression increased from day 9 after transplantation. Moreover, altered expression of bcl-2 and bax was accompanied by the increased proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). Time-dependent dephosphorylation of Rb, followed by proteolytic cleavage, was also observed from day 9 after transplantation. The data indicate that the caspase-3 activation and cleavage of Rb protein may represent important steps in the regulation pathway of bax-mediated spontaneous apoptosis. Interestingly, the time-dependent activation of spontaneous apoptosis was almost simultaneous with the induction of differentiation and increased expression of several differentiation-associated regulatory proteins. An increased expression of cyclin D1 and cyclin-dependent kinase-5 (cdk5) was observed from day 9 after transplantation, whereas only slight alteration of cdk4 expression was found. The time-dependent activation of cyclin D1 and cdk5 preceded both the induction of ladder-type DNA fragmentation and increased keratin pearl formation. Furthermore, MCM3 was cleaved early in spontaneous apoptosis and differentiation. Our observations suggest the involvement of cyclin D1-cdk5 overexpression and MCM3 cleavage in bax-mediated spontaneous apoptosis and differentiation in A253 xenografts. P53 and WAF1 proteins were not expressed in the xenografts, indicating that the changes in the regulatory proteins during apoptosis and differentiation were not p53 or WAF1 dependent.
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PMID:Involvement of cyclin D1-cdk5 overexpression and MCM3 cleavage in bax-associated spontaneous apoptosis and differentiation in an A253 human head and neck carcinoma xenograft model. 1049 26

Ligation of the Fas cell surface receptor leads to activation of caspases and subsequent apoptosis. Members of the Bcl-2 family of proteins control the cellular commitment to apoptosis, although their role in Fas-induced apoptosis is ill-defined. In this report we demonstrate that the pro-apoptotic protein, Bax, translocates from the cytosol specifically to the mitochondria following Fas ligation in MCF10A1 breast epithelial cells. Bax translocation was dependent on caspase activation, and preceded the release of cytochrome c and loss of mitochondrial respiratory activity. Bax translocation occurred in concert with activation of downstream caspases as determined by cleavage of a synthetic substrate, proteolysis of poly(ADP-ribose) polymerase, and processing of procaspase-3 and -7. Overexpression of the anti-apoptotic protein, Bcl-2, prevented Bax insertion, cytochrome c release, complete processing of caspase-3 and -7, and full activation of DEVD-specific cleavage activity. These data establish a role for Bax mitochondrial insertion during Fas-mediated apoptosis, and support a model in which Bax insertion amplifies the Fas apoptotic cascade through cytochrome c release and complete processing of caspases-3 and -7. In addition, our findings indicate that prevention of Bax insertion into the mitochondria represents a novel mechanism by which Bcl-2 inhibits Fas-induced apoptosis.
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PMID:Bax membrane insertion during Fas(CD95)-induced apoptosis precedes cytochrome c release and is inhibited by Bcl-2. 1055 88

Cardiac myocyte apoptosis is potentially important in many cardiac disorders. In other cells, Bcl-2 family proteins and mitochondrial dysfunction are probably key regulators of the apoptotic response. In the present study, we characterized the regulation of antiapoptotic (Bcl-2, Bcl-xL) and proapoptotic (Bad, Bax) Bcl-2 family proteins in the rat heart during development and in oxidative stress-induced apoptosis. Bcl-2 and Bcl-xL were expressed at high levels in the neonate, and their expression was sustained during development. In contrast, although Bad and Bax were present at high levels in neonatal hearts, they were barely detectable in adult hearts. We confirmed that H(2)O(2) induced cardiac myocyte cell death, stimulating poly(ADP-ribose) polymerase proteolysis (from 2 hours), caspase-3 proteolysis (from 2 hours), and DNA fragmentation (from 8 hours). In unstimulated neonatal cardiac myocytes, Bcl-2 and Bcl-xL were associated with the mitochondria, but Bad and Bax were predominantly present in a crude cytosolic fraction. Exposure of myocytes to H(2)O(2) stimulated rapid translocation of Bad (<5 minutes) to the mitochondria. This was followed by the subsequent degradation of Bad and Bcl-2 (from approximately 30 minutes). The levels of the mitochondrial membrane marker cytochrome oxidase remained unchanged. H(2)O(2) also induced translocation of cytochrome c from the mitochondria to the cytosol within 15 to 30 minutes, which was indicative of mitochondrial dysfunction. Myocytes exposed to H(2)O(2) showed an early loss of mitochondrial membrane potential (assessed by fluorescence-activated cell sorter analysis) from 15 to 30 minutes, which was partially restored by approximately 1 hour. However, a subsequent irreversible loss of mitochondrial membrane potential occurred that correlated with cell death. These data suggest that the regulation of Bcl-2 and mitochondrial function are important factors in oxidative stress-induced cardiac myocyte apoptosis.
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PMID:Regulation of bcl-2 family proteins during development and in response to oxidative stress in cardiac myocytes: association with changes in mitochondrial membrane potential. 1055 33


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