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)

A number of oncogenes alter the regulation of the cell cycle and cell death, contributing to the altered growth of tumours. Expression of the v-Src oncoprotein in Rat-1 fibroblasts prevented cell cycle exit in response to growth factor withdrawal. Here we investigated whether survival of v-Src transformed cells in low serum is dependent on v-Src activity. We used a temperature sensitive v-Src to study the effect inactivating v-Src on transformed cells growing under low serum conditions. We found when we switched off v-Src the cells died by apoptosis characterised by activation of caspases and the stress-activated kinases, JNK (Jun N-terminal kinase) and p38 MAP (mitogen activated protein) kinase. We were able to prevent cell death by addition of serum or overexpression of Bcl-2. Thus v-Src transformed Rat-1 cells can be protected from apoptosis by serum, v-Src, or Bcl-2. We investigated how v-Src protects from apoptosis under these conditions. Amongst other effects, v-Src activates two kinases which have been shown to protect cells from apoptosis, phosphatidylinositol 3-kinase (PI3-K) and extracellular signal-regulated kinase (ERK1/2). We found that switching off v-Src led to a decrease in the activity of both PI3-K and ERK1/2, however, we found that adding a specific inhibitor of PI3-K (LY294002) to v-Src transformed Rat-1 cells grown in low serum induced apoptosis while a specific ERK kinase (MEK1) inhibitor (PD98059) had no effect. This suggests that v-Src protects from apoptosis under low serum conditions by activating PI3-K.
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PMID:Regulation of both apoptosis and cell survival by the v-Src oncoprotein. 1091 42

Apoptosis of arterial cells induced by oxidized low density lipoproteins (OxLDL) is thought to contribute to the progression of atherosclerosis. However, most data on apoptotic effects and mechanisms of OxLDL were obtained with extensively oxidized LDL unlikely to occur in early stages of atherosclerotic lesions. We now demonstrate that mildly oxidized LDL generated by incubation with oxygen radical-producing xanthine/xanthine oxidase (X/XO) induces apoptosis in primary cultures of human coronary endothelial and SMC, as determined by TUNEL technique, DNA laddering, and FACS analysis. Apoptosis was markedly reduced when X/XO-LDL was generated in the presence of different oxygen radical scavengers. Apoptotic signals were mediated by intramembrane domains of both Fas and tumor necrosis factor (TNF) receptors I and II. Blocking of Fas ligand (FasL) reduced apoptosis by 50% and simultaneous blocking of FasL and TNF receptors by 70%. Activation of apoptotic receptors was accompanied by an increase of proapoptotic and a decrease in antiapoptotic proteins of the Bcl-2 family and resulted in marked activation of class I and II caspases. Mildly oxidized LDL also activated MAP and Jun kinases and increased p53 and other transcription factors (ATF-2, ELK-1, CREB, AP-1). Inhibitors of Map and Jun kinase significantly reduced apoptosis. Our results provide the first evidence that OxLDL-induced apoptosis involves TNF receptors and Jun activation. More important, they demonstrate that even mildly oxidized LDL formed in atherosclerotic lesions may activate a broad cascade of oxygen radical-sensitive signaling pathways affecting apoptosis and other processes influencing the evolution of plaques. Thus, we suggest that extensive oxidative modifications of LDL are not necessary to influence signal transduction and transcription in vivo.
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PMID:Mildly oxidized low density lipoprotein activates multiple apoptotic signaling pathways in human coronary cells. 1102 84

Breast tumor cells are relatively refractory to apoptosis in response to modalities which induce DNA damage such as ionizing radiation and the topoisomerase II inhibitor, adriamycin. Various factors which may modulate the apoptotic response to DNA damage include the p53 status of the cell, levels and activity of the Bax and Bcl-2 families of proteins, activation of NF-kappa B, relative levels of insulin like growth factor and insulin-like growth factor binding proteins, activation of MAP kinases and PI3/Akt kinases, (the absence of) ceramide generation and the CD95 (APO1/Fas) signaling pathway. Prolonged growth arrest associated with replicative senescence may represent an alternative and reciprocal response to DNA-damage induced apoptosis that is p53 and/or p21waf1/cip1 dependent while delayed apoptosis may occur in p53 mutant breast tumor cells which fail to maintain the growth-arrested state. Clearly, the absence of an immediate apoptotic response to DNA damage does not eliminate other avenues leading to cell death and loss of self-renewal capacity in the breast tumor cell. Nevertheless, prolonged growth arrest (even if ultimately succeeded by apoptotic or necrotic cell death) could provide an opportunity for subpopulations of breast tumor cells to recover proliferative capacity and to develop resistance to subsequent clinical intervention.
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PMID:Growth arrest and cell death in the breast tumor cell in response to ionizing radiation and chemotherapeutic agents which induce DNA damage. 1107 87

A panel of human B-lineage lymphoma cell lines differing in cancer drug-resistance status and Bcl-2/Bax expression were used to study the contribution of mitochondrial-based perturbations and regulation in differential induction of apoptosis. Mitochondrial dysfunction was induced in cells by the uncoupler carbonyl cyanide m-chlorophenylhydrazone (mClCCP) and the respiratory chain inhibitor antimycin A. Cells were then assayed for early changes in MAP kinase signaling and subsequent induction of apoptosis. The cancer drug-resistant cell lines EW36 and CA46, overexpressing Bcl-2 and deficient in Bax, respectively, were both resistant to mitochondrial toxicant-induced cleavage of poly(ADP-ribose) polymerase (PARP) and morphologically detectable apoptotic cell death. In contrast, cancer drug-sensitive ST486 cell line, with low Bcl-2 expression, was sensitive to PARP cleavage and apoptosis engagement. Interestingly, mClCCP induced twofold more apoptosis than antimycin A in the ST486 cells. Exposure to the mitochondrial toxicants resulted in the early and preferential activation of the ERK and p38 MAP kinase pathways in only the drug-sensitive ST486 cell line, with mClCCP more potent than antimycin A. Specific inhibition of the p38 pathway augmented baseline and mClCCP-induced apoptosis. These results show that multi-drug-resistant and -sensitive B-lineage cells are also resistant and sensitive to compounds inducing mitochondrial dysfunction. The differential sensitivity to mitochondrial toxicant effects involved regulation by MAP kinases, since ERK and p38 were found to be preferentially activated only in the drug-sensitive B-lineage cells. Modulation of the p38 signaling pathway altered the sensitivity of cells to mitochondrial stress and may play a more general role in regulating the sensitivity of B-lineage cells to drugs and environmental toxicants.
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PMID:Differential induction of apoptosis and MAP kinase signaling by mitochondrial toxicants in drug-sensitive compared to drug-resistant B-lineage lymphoid cell lines. 1148 85

Bcl-2 has been reported to inhibit neurotoxicity induced by cisplatin. However, neither the mechanism of cisplatin-induced neurotoxicity nor the mechanism by which Bcl-2 confers neuroprotection is clear. In this study, the signaling pathways involved in cisplatin-induced neurotoxicity were examined using a rat neuroblastoma cell line, B104. Treatment of B104 cells with cisplatin induced apoptosis, accompanying the accumulation of p53 and Bax protein. Interestingly, extracellular signal-regulated kinase 1/2 (ERK1/2) activities of MAP kinases were markedly enhanced prior to cisplatin-induced accumulation of p53 and Bax. Inhibition of ERK1/2 activities using PD98059, a selective MEK inhibitor, blocked the apoptotic cell death preventing cisplatin-induced accumulation of p53 and Bax. These results suggest that ERK mediates cisplatin-induced p53 activation to trigger apoptosis in B104 cells. Overexpression of Bcl-2 in B104 cells resulted in the complete resistance to cisplatin-induced apoptosis blocking ERK activation and the subsequent signaling pathway of p53. Our study clearly demonstrates that the action site of Bcl-2 localizes upstream of ERK in cisplatin-induced apoptotic signaling pathway.
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PMID:Bcl-2 blocks cisplatin-induced apoptosis by suppression of ERK-mediated p53 accumulation in B104 cells. 1153 34

The novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) inhibits cell proliferation and is a very effective inducer of apoptosis in a variety of carcinoma cell lines. In order to obtain greater insight into the mechanism of AHPN-induced growth arrest and apoptosis, we began to examine AHPN-induced changes in gene expression by cDNA array screening using human lung carcinoma H460 cells. This analysis identified several AHPN-inducible genes, including the immediate-early genes Egr-1 and Nur77. AHPN was able to increase Egr-1 and Nur77 mRNA expression and protein in a variety of carcinoma cell lines. This induction appeared to be regulated at the transcriptional level and was specific for AHPN since an RAR- and an RXR-selective retinoid were inactive. These results suggest that the induction of Egr-1 and Nur77 by AHPN is independent of nuclear retinoid receptors and involves a novel mechanism. Overexpression of Bcl-2, which inhibits AHPN-induced apoptosis but not growth arrest in human T cell lymphoma Molt-4 cells, did not block the induction of immediate-early gene expression. Treatment of H460 cells with AHPN induced activation of the p38 MAP-kinase but not the ERK1/2 signaling pathway. However, inhibition of the ERK1/2 signaling pathway by PD98059 blocked the induction of Egr-1 and Nur77 mRNA while the p38 MAPK inhibitor PD169316 had little effect. Expression of a dominant-negative ERK1 completely abolished the increase in Egr-1 mRNA. Treatment with MAPK inhibitors or expression of dnERK1 reduced but did not block AHPN-induced apoptosis. Our results suggest that the induction of Egr-1 in H460 by AHPN requires active ERK1/2 and is independent of p38 activation. Egr-1, in cooperation with several other growth-suppressor proteins, is likely involved in AHPN-induced inhibition of cell growth and cell death.
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PMID:Induction of Egr-1 expression by the retinoid AHPN in human lung carcinoma cells is dependent on activated ERK1/2. 1155 93

In this investigation, the effects and potential mechanisms of female sex steroid action on proliferation, cell cycling, and apoptosis in Jurkat CD4 + T lymphocytes were examined. 17-beta-Estradiol (estrogen) inhibited Jurkat T cell proliferation, stimulated accumulation of cells in S and G2/M phases of the cell cycle, and induced apoptosis over 72 h in a dose-dependent manner. 4-Pregnene-3,20-dione (progesterone) did not induce redistribution of the cells in the cell cycle but did induce cytostasis and slightly increased apoptosis. Simultaneous staining with anti-BrDU and propidium iodide indicated that estrogen-treated Jurkat T cells proceeded through S phase prior to apoptosis. Progesterone halted cell cycle progression; cells did not progress through S phase or incorporate BrDU. Both hormones decreased the percentage of cells in S or G2/M expressing cyclin A protein, but did not affect cyclin D protein expression. Cyclin A mRNA was markedly decreased by estrogen. Bcl-2 protein and mRNA were also reduced in estrogen but not progesterone-treated Jurkat T lymphocytes. This data shows that high concentrations of estrogen or progesterone significantly suppress lymphoproliferation in association with suppression of cyclin A. Additionally, bcl-2 protein levels were suppressed in association with estrogen-induced apoptosis. These findings demonstrate direct, hormone-specific effects on lymphocytes that may provide insight into their role in immunomodulation or the development of autoimmunity.
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PMID:17-beta-estradiol alters Jurkat lymphocyte cell cycling and induces apoptosis through suppression of Bcl-2 and cyclin A. 1160 22

Oxidative base (8-oxoguanine) damage, DNA fragmentation, and apoptosis occurred among ovarian surface epithelial cells within the formative site of ovulation in sheep. The incidence of 8-oxoguanine adducts in surviving antiapoptotic Bcl-2/base excision repair polymerase beta-positive cells at the margins of ruptured follicles (which avoid the focal point of the ovulatory assault) was intermediate between apoptotic and outlying healthy epithelium. Cells containing perturbations to DNA expressed the tumor suppressor p53. Localized reactions of DNA injury and programmed cellular death were averted by ovulation blockade with indomethacin. Progesterone enhanced the biosynthesis of polymerase beta in ovarian surface epithelial cells exposed in vitro to a sublethal concentration of H(2)O(2). Ovulation is a putative etiological factor in common epithelial ovarian cancer. A genetically altered progenitor cell, with unrepaired DNA, but not committed to death, could give rise to a transformed phenotype that is hence propagated upon healing of the ovulatory wound; it appears that this incongruity is normally reconciled by up-regulation of the base excision repair pathway during the ensuing luteal phase.
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PMID:Ovulation-induced DNA damage in ovarian surface epithelial cells of ewes: prospective regulatory mechanisms of repair/survival and apoptosis. 1167 58

Estrogen replacement therapy is associated with improvement of cognitive deficits and reduced incidence of Alzheimer's disease. To compare the impact of therapeutically relevant progestins on estrogen-induced neuroprotection, we treated primary hippocampal neuron cultures with 17beta-E2 and progestin, alone and in combination, 48 h before glutamate insult. Estrogen, progesterone, and 19-norprogesterone, alone or in combination, protected against glutamate toxicity. In contrast, medroxyprogesterone acetate (MPA) failed to protect against glutamate toxicity. Not only was MPA an ineffective neuroprotectant but it attenuated the estrogen- induced neuroprotection when coadministered. We addressed the role of MAPK activation in neuroprotection by ovarian steroids. Estrogen and all three progestins tested, alone or in combination, activated MAPK, indicating another mechanism of protection. Bcl-2 expression has been shown to prevent cell death and is up-regulated by 17beta-E2. Progesterone and 19-norprogesterone, alone or in combination with estrogen, increased Bcl-2 expression. In contrast, MPA blocked estrogen-induced Bcl-2 expression when coadministered. These results may have important implications for the effective use of hormone replacement therapy in the maintenance of neuronal function during menopause and aging and for protection against neurodegenerative diseases such as Alzheimer's disease.
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PMID:Impact of progestins on estrogen-induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. 1175 11

IL-7 delivers survival signals to cells at an early stage in lymphoid development. In the absence of IL-7, pro-T cells undergo programmed cell death, which has previously been associated with a decline in Bcl-2 and translocation of Bax from cytosol to mitochondria. A new, earlier feature of IL-7 withdrawal was identified using an IL-7-dependent thymocyte line. We observed that withdrawal of IL-7 induced increased expression of jun and fos family member genes including c-jun, junB, junD, c-fos and fra2. This transient response peaked 3-4 h after IL-7 was withdrawn and resulted in increased DNA-binding activity of AP-1 and in a change in the composition of the Jun/Fos family dimers shown by electrophoretic mobility shift and supershift assays. Induction of jun and fos genes and the increased DNA-binding activity of AP-1 were attributable to the phosphorylation-induced activation of the stress kinases p38 and JNK and were blocked by the chemical kinase inhibitors SB203580 and SB202190. The stress response contributed to cell death following IL-7 withdrawal as shown by blocking the activity of the stress (MAP) kinases or by blocking the production of c-Jun and c-Fos using antisense oligonucleotides.
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PMID:IL-7 withdrawal induces a stress pathway activating p38 and Jun N-terminal kinases. 1203 57


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