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)

Gossypol, a male contraceptive drug, has been demonstrated to have antiproliferative and antimetastatic effects on many kinds of cancer cells in vitro. HT-29 human carcinoma cell line is one of the most susceptible cell lines to gossypol-induced cell death. Here, it is shown that treatment of HT-29 cells with gossypol not only induces cell cycle arrest on the G0/G1 phase, but also induces apoptosis. With a serial of Western blot analysis, it is revealed that gossypol-induced cell cycle arrest is involved in P21 up-regulation and cyclin D1 down-regulation; gossypol-induced apoptosis triggers down-regulation of anti-apoptosis Bcl-2 members: Bcl-X(L), Bag-1 and Mcl-1, up-regulation of pro-apoptosis Bcl-2 member Bak, activation of caspase-3, -6, -7, -8, and -9, up-regulation of Apaf-1, release of cytochrome c (cyto-c) from mitochondria, and activation of both DFF45 and PARP. Taken together, gossypol-induced cell death initiates extensive alterations of cell cycle and apoptosis proteins. Gossypol-induced apoptosis of HT-29 cells is through first the mitochondrial pathway, then the death receptor pathway, and the mitochondria pathway is, at least in part, involved in cyto-c release.
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PMID:Molecular mechanism of gossypol-induced cell growth inhibition and cell death of HT-29 human colon carcinoma cells. 1281 69

The cyclooxygenase (COX)-2 inhibitor Celecoxib may inhibit cancer cell growth independently of its capacity to block the COX-2 enzyme. The growth inhibitory effect had been attributed to its pro-apoptotic effects. However, the molecular details of Celecoxib-induced apoptosis have not been analyzed yet. To differentiate between death receptor and mitochondrial signaling pathways, induction of apoptosis upon treatment with Celecoxib was tested in Jurkat T- and BJAB B-lymphoma cell lines with defects in either pathway. Celecoxib-induced dose- and time-dependent apoptosis in Jurkat and BJAB cells involving i) activation of caspases-9, -8, and -3, ii) cleavage of poly(ADP-ribose) polymerase and inhibitor of caspase-activated DNAase, iii) breakdown of the mitochondrial membrane potential, and iv) release of cytochrome c. Lack of Fas-associated death domain protein (FADD), overexpression of a dominant negative FADD, lack of caspase-8, and treatment with caspase-8-specific inhibitors had no influence on Celecoxib-induced apoptosis. In contrast, overexpression of a dominant negative caspase-9 or pharmacological inhibition of caspase-9 strongly interfered with Celecoxib-induced cell death. Furthermore, expression of Apaf-1 was required for Celecoxib-induced apoptosis. Importantly, Bcl-2 overexpression did not abrogate caspase activation, mitochondrial alterations, and apoptosis upon Celecoxib treatment while inhibiting radiation induced apoptosis. In conclusion, Celecoxib induces apoptosis via a novel apoptosome-dependent but Bcl-2-independent mitochondrial pathway.
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PMID:Celecoxib activates a novel mitochondrial apoptosis signaling pathway. 1282 3

FL5.12 pro-B lymphoma cells utilize the mitochondrial pathway to apoptosis in response to tumor necrosis factor (TNF) receptor occupation, yet high levels of the Bcl-2 family antiapoptotic protein, Bcl-x(L), fail to protect these cells against TNF-receptor-activated death. Bcl-x(L) expression delays, but does not totally block, the release of mitochondrial cytochrome c (cyt c) in these cells in response to TNFalpha-induced apoptosis and caspase-9 is processed prior to mitochondrial cyt c release under these circumstances. Early processing of caspase-9 also occurred in Apaf-1 knockout murine fibroblasts in response to TNF-receptor occupation. A caspase-9-specific inhibitor was more effective in delaying the progression of apoptosis in the FL5.12 Bcl-x(L) cells than was an inhibitor specific to caspase-3. Furthermore, downregulation of caspase-9 levels by RNA interference resulted in partial protection of these cells against TNF-receptor-activated apoptosis, indicating that caspase-9 activation contributed to early amplification of the caspase cascade. Consistent with this, proteolytic processing of caspase-9 was observed prior to processing by caspase-3, suggesting that caspase-3 was not responsible for early caspase-9 activation. We show that murine caspase-9 is efficiently processed by active caspase-8 at SEPD, the motif at which caspase-9 autoprocesses following its recruitment to the apoptosome. Our results suggest that, in addition to processing procaspase-3 and the BH3 protein Bid, active caspase-8 can cleave and activate procaspase-9 in response to TNF receptor crosslinking in murine cells.
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PMID:Caspase-9 is activated in a cytochrome c-independent manner early during TNFalpha-induced apoptosis in murine cells. 1293 75

Mitochondrial outer-membrane permeabilization by pro-apoptotic Bcl-2 family members plays a crucial role in apoptosis induction. However, whether this directly causes the release of the different mitochondrial apoptogenic factors simultaneously is currently unknown. Here we report that in cells or with isolated mitochondria, pro-apoptotic Bcl-2 proteins cause the release of cytochrome c, Smac/Diablo and HtrA2/Omi but not endonuclease G (EndoG) and apoptosis-inducing factor (AIF). In cells treated with Bax/Bak-dependent pro-apoptotic drugs, neither the caspase inhibitor zVAD-fmk nor loss of Apaf-1 affected the efflux of cytochrome c, Smac/Diablo and HtrA2/Omi, but both prevented the release of EndoG and AIF. Our findings identify the mitochondrial response to pro-apoptotic stimuli as a selective process leading to a hierarchical ordering of the effectors involved in cell death induction. Moreover, as in Caenorhabditis elegans, EndoG and AIF act downstream of caspase activation. Thus EndoG and AIF seem to define a 'caspase-dependent' mitochondria-initiated apoptotic DNA degradation pathway that is conserved between mammals and nematodes.
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PMID:Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization. 1294 91

CED-4, a pro-apoptotic factor in Caenorhabditis elegans, activates the cell death protease CED-3. CED-9 directly binds to CED-4 and represses this. However, it has remained unclear whether a mammalian CED-9 homologue, Bcl-XL, inhibits the function of the mammalian CED-4 homologue, Apaf-1, by direct binding. To analyze the interaction, we adopted a yeast two-hybrid system. Since Bcl-XL and the CED-4-like portion of Apaf-1 failed to exhibit a positive result in the assay, we prepared "fragment libraries" of bcl-XL or apaf-1 cDNA. By screening of the apaf-1 "fragment library," we obtained nine clones interacting with Bcl-XL, all containing the same region within the ATPase domain, designated BBR: the Bcl-XL binding region. Binding of BBR to Bcl-XL was also confirmed by immunoprecipitation assays. Bcl-2, Bcl-w, A1/Bfl-1, and Boo/Diva failed to show the same capacity for binding to BBR as Bcl-XL. These results indicate that Bcl-XL directly binds to a specific region in Apaf-1.
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PMID:Identification of a Bcl-XL binding region within the ATPase domain of Apaf-1. 1296 20

Adenosine deaminase (ADA) catalyzes the conversion of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. ADA-deficient individuals suffer from severe combined immunodeficiency and are unable to produce significant numbers of mature T or B lymphocytes. This occurs as a consequence of the accumulation of ADA substrates or their metabolites. dATP is a candidate toxic metabolite because its concentration in RBCs of ADA-deficient patients correlates with the severity of disease. Murine fetal thymic organ culture (FTOC) under ADA-deficient conditions can be used as a model system to investigate the biochemical mechanism responsible for the inhibition of thymopoiesis. In ADA-deficient FTOCs initiated at day 15 of gestation, thymocyte development was arrested at the CD4(-)CD8(-)CD44(lo)CD25(+) to CD4(-)CD8(-)CD44(lo)CD25(-) transition. Apoptosis appeared to be involved because the cultures could be rescued by the pan-caspase inhibitor zVADfmk, a Bcl-2 transgene, or deletion of apoptotic protease activating factor-1. As in ADA-deficient patients, dATP was also elevated in ADA-deficient FTOCs. dATP levels were normalized and thymocyte development was rescued in cultures treated with an inhibitor of adenosine kinase, the enzyme that phosphorylates deoxyadenosine to dAMP. zVADfmk also prevented the accumulation of dATP in ADA-deficient FTOCs, suggesting that deoxyadenosine was derived from thymocytes undergoing apoptosis as a consequence of failing the beta selection checkpoint. In contrast, dATP levels remained elevated in ADA-deficient FTOCs with fetal thymuses from Bcl-2 transgenic mice. These data suggest that thymocyte apoptosis as a consequence of failing developmental checkpoints involves one or more caspases that are not regulated by Bcl-2.
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PMID:Mechanisms of apoptosis in developing thymocytes as revealed by adenosine deaminase-deficient fetal thymic organ cultures. 1455 39

Neurons may die as a normal physiological process during development or as a pathological process in diseases. The best-understood mechanism of neuronal cell death is apoptosis, which is regulated by an evolutionarily conserved cellular pathway that consists of the caspase family, the Bcl-2 family, and the adaptor protein Apaf-1. Apoptosis, however, may not be the only cellular mechanism that regulates neuronal cell death. Neuronal cell death may exhibit morphological features of autophagy or necrosis, which differ from that of the canonical apoptosis. This review evaluates the evidence supporting the existence of alternative mechanisms of neuronal cell death and proposes the possible existence of an evolutionarily conserved pathway of necrosis.
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PMID:Diversity in the mechanisms of neuronal cell death. 1455 17

Neural precursor cells (NPCs) critically regulate brain morphogenesis and recent studies have revealed an unexpectedly high frequency of NPC chromosomal abnormalities and apoptosis in the developing brain. We have shown previously that the apoptotic response of NPCs to genotoxic agents is dependent on p53 and caspase-9, but not Bax or caspase-3 expression. In this study, we found that NPCs deficient in Apaf-1, or both the pro-apoptotic multidomain Bcl-2 family members Bax and Bak, were resistant to cytosine arabinoside and gamma-irradiation-induced apoptosis. Inhibitors of gene transcription, protein translation, and caspase activity also blocked genotoxin-induced NPC apoptosis. Although caspase-3 and caspase-6 were both cleaved in response to DNA damage, neither of these effector caspases was critical for apoptosis. Genotoxin-induced NPC death was accompanied by the generation of reactive oxygen species and could be inhibited by several known antioxidants. Conversely, DNA damage-induced reactive oxygen species generation was inhibited significantly by gene disruption of p53, Apaf-1, or caspase-9, and combined deficiency of Bax and Bak, but not by caspase-3 or caspase-6 deficiency. These studies suggest that caspase-9 activation is both necessary and sufficient for genotoxin-induced neural precursor cell reactive oxygen species generation and death.
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PMID:Caspase regulation of genotoxin-induced neural precursor cell death. 1459 20

Apoptosis is defined on the basis of morphological changes like nuclear fragmentation and chromatin condensation, which are dependent on caspases. Many forms of caspase-independent cell death have been reported, but the mechanisms are still poorly understood. We found that hypoxic cell death was independent of caspases and was associated with significant nuclear shrinkage. Neither Bcl-2 nor Apaf-1 deficiency prevented hypoxic nuclear shrinkage. To understand the molecular mechanism of the nuclear shrinkage, we developed an in vitro system using permeabilized cells, which allowed us to purify a novel member of the phospholipase A2 (PLA2) family that induced nuclear shrinkage. Purified PLA2 induced nuclear shrinkage in our permeabilized cell system. PLA2 inhibitors prevented hypoxic nuclear shrinkage in cells and cell death. Hypoxia caused elevation of PLA2 activity and translocation of intracellular PLA2s to the nucleus. Knockdown of the Ca2+-independent PLA2 delayed nuclear shrinkage and cell death. These results indicate that Ca2+-independent PLA2 is crucial for a caspase-independent cell death signaling pathway leading to nuclear shrinkage.
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PMID:PLA2 activity is required for nuclear shrinkage in caspase-independent cell death. 1467 6

We studied the mechanism of intra-mitochondrial death initiator caspase-9 activation by a redox response, in which hydrogen peroxide (H(2)O(2)) caused a subtle decrease in the inner membrane potential (Deltapsim) with little evidence of cytochrome c release. Initiation of the intra-mitochondrial autocleavage of procaspase-9 preceded the onset of caspase cascade induction in the cytosol. Purified mitochondria demonstrated procaspase-9 processing and releasing abilities when exposed to H(2)O(2). Bcl-2 overexpression caused accumulation of the active form caspase-9 in the mitochondria, rendering the cells resistant to the redox stress. Intriguingly, disulfide-bonded dimers of autoprocessed caspase-9 were generated in the mitochondria in the pre-apoptotic phase. Using a substrate-analog inhibitor, dimer formation of procaspase-9 was also detectable inside the mitochondria. Furthermore, thiol reductant thioredoxin blocked the caspase-9 activation step and the cell death induction. Thus, redox stress-responsive thiol-disulfide converting reactions in the mitochondrion seemed to mediate procaspase-9 assembly that allows autoprocessing. This study offers an explanation for the recent observation that Apaf-1-null cells can execute apoptosis, which can be blocked by Bcl-2, and supports the proposition that the cytochrome c-Apaf-1-procaspase-9 complex functions in the caspase amplification rather than in its initiation.
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PMID:Dimerization and processing of procaspase-9 by redox stress in mitochondria. 1474 74


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