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 the basal activity of the serine/threonine protein kinase, protein kinase C (PKC) in the regulation of anti-CD95-induced apoptosis in Jurkat T cells was investigated. The PKC-specific inhibitor GF 109203X and the proposed cPKC-specific inhibitor Go 6976, in a concentration-dependent manner, increased the percentage of cells undergoing apoptosis induced by anti-CD95 mAb as demonstrated by propidium iodide (PI) staining, TUNEL assay and DNA fragmentation by gel electrophoresis. Furthermore, Go 6976 and GF 109203X abrogated phorbol myristate acetate-induced inhibition of anti-CD95-induced apoptosis. To examine the molecular mechanism by which PKC modulates anti-CD95-induced apoptosis, the effects of Go 6976 on known effector and regulatory molecules of cell death were studied. Increased recruitment of cells undergoing apoptosis was associated with enhanced anti-CD95-induced proteolytic cleavage of the most receptor-proximal cysteine protease caspase-8, subsequent cleavage and activation of the machinery protease caspase-3, and cleavage of the caspase substrates DNA-dependent protein kinase catalytic subunit, poly-(ADP-ribose) polymerase and lamin B1. CD95 and FADD protein levels in Jurkat T cells were not altered by Go 6976 treatment. In addition, Go 6976 did not alter protein levels and subcellular distribution of the anti-apoptotic molecules Bcl-2 and Bcl-xL. These data suggest indirectly that basal PKC activity acts at an early stage in the anti-CD95-induced caspase pathway to attenuate subsequent activation of downstream effector molecules and associated apoptosis in Jurkat T cells.
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PMID:Inhibition of the protein kinase C pathway promotes anti-CD95-induced apoptosis in Jurkat T cells. 970 Oct 26

Some cytokines can prolong cell survival in hematolymphoid cells and thus may be crucial for regulation of hematolymphoid cell numbers. It has been shown that mitogenic cytokines can induce not only cellular proliferation but also cellular survival by inhibiting apoptosis in hematolymphoid cells. The signals transduced by these cytokines eventually go to the nucleus and induce expression of their specific target genes. In this context, the induction of anti-apoptotic molecules such as Bcl-2 oncoprotein and BAG-1 protein seems to be a key event for the anti-apoptotic function of cytokines. In T lymphocytes, the interaction of interleukin-2 (IL-2) with its receptor (IL-2R) induces both cellular proliferation and cellular survival. The IL-2R consists of three subunits, i.e., IL-2Ralpha, IL-2R(beta)c, and IL-2R(gamma)c chains. Structure-function analysis of the IL-2R(beta)c chain has revealed that there are at least two functional domains within the subunit. The serine-rich (S) region but not the acidic (A) region within the (beta)c chain is responsible for the mitogenic signaling of IL-2R. The S region is also crucial for the cellular survival signaling, which include the induction of anti-apoptotic gene expressions bcl-2 and bag-l. However, the cellular survival signaling is segregated from the mitogenic signaling in independence from the Jak-family protein kinase activation and rapamycin sensitivity. Segregation of the two signaling pathways of a cytokine receptor has also been shown in receptors of the other mitogenic cytokines. Current topics regarding signal transductions of cytokine receptors responsible for the suppression of apoptosis are discussed in this review.
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PMID:BAG-1 and Bcl-2 in IL-2 signaling. 971 11

The mechanism by which early lymphoid cells are selectively transformed by v-Abl is currently unknown. Previous studies have shown constitutive activation of IL-4 and IL-7 signaling pathways, as measured by activation of Janus protein kinase (JAK)1, JAK3, STAT5, and STAT6, in pre-B cells transformed by v-Abl. To determine whether activation of these cytokine signaling pathways by v-Abl is important in the cellular events induced by the Abelson murine leukemia virus, the effects of IL-4 and IL-7 on pre-B cells transformed with a temperature-sensitive v-Abl mutant were examined. Whereas IL-4 had little or no effect, IL-7 delayed both the apoptosis and cell cycle arrest that occur upon v-Abl kinase inactivation. IL-7 also delayed the decreases in the levels of c-Myc, Bcl-2, and Bcl-xL that occur upon loss of v-Abl kinase activity. IL-7 did not maintain v-Abl-mediated differentiation arrest of the pre-B cells, as activation of NF-kappaB and RAG gene transcription was unaffected by IL-7. These results identify a potential role for IL-7 signaling pathways in transformation by v-Abl while demonstrating that a combination of IL-4 and IL-7 signaling cannot substitute for an active v-Abl kinase in transformed pre-B cells.
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PMID:IL-7 reconstitutes multiple aspects of v-Abl-mediated signaling. 979 89

Prior investigations document that proliferative signaling cascades, under some circumstances, initiate apoptosis, although mechanisms that dictate the final outcome are largely unknown. In COS-7 cells, ceramide signals Raf-1 activation through Ras (Zhang, Y., Yao, B., Delikat, S., Bayoumy, S., Lin, X. H., Basu, S., McGinley, M., Chan-Hui, P. Y., Lichenstein, H., and Kolesnick, R. (1997) Cell 89, 63-72), but not apoptosis. However, expression of small amounts of the pro-apoptotic Bcl-2 family member, BAD, conferred ceramide-induced apoptosis onto COS-7 cells. Ceramide signaled apoptosis in BAD-expressing cells by a pathway involving sequentially kinase suppressor of Ras (KSR)/ceramide-activated protein kinase, Ras, c-Raf-1, and MEK1. Downstream, this pathway linked to BAD dephosphorylation at serine 136 by prolonged inactivation of Akt/PKB. Further, mutation of BAD at serine 136 abrogated ceramide signaling of apoptosis. The present study indicates that when ceramide signals through the Ras/Raf cascade, the availability of a single target, BAD, may dictate an apoptotic outcome.
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PMID:BAD enables ceramide to signal apoptosis via Ras and Raf-1. 980 8

Bcl-2, Bax and p53 gene products have been linked to programmed cell death pathways. p21WAF1 has been shown to mediate p53-induced cell cycle arrest and to inhibit cyclin-dependent kinase activity. We have analysed the expression of these genes and apoptosis induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in several human breast cancer cell line. We found up-regulation of p21WAF1 and Bax expressions, however, the expressions of p53 and Bcl-2 genes remained unchanged in TPA-treated cells. Furthermore, DNA ladder formation and PARP cleavage were observed after treatment for 24 h, indicating apoptotic cell death. Flow cytometry with 7-amino actinomycin D staining showed that the number of apoptotic cells increased with longer treatment of TPA. From these results, we conclude that TPA is not only a tumor promoter, but also induces apoptosis in breast cancer cells. TPA-induced apoptosis appears to be mediated through a p53-independent pathway, and the up-regulation of p21WAF1 and Bax may be the molecular mechanisms by which TPA induces apoptosis.
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PMID:Induction of apoptosis in breast cancer cells by TPA. 987 97

It has been suggested that overexpression of the Bcl-2 oncoprotein in human cancer cells contributes to their resistance to apoptosis induced by chemotherapy. We report here that a novel dipeptidyl proteasome inhibitor, CEP1612, at low concentrations rapidly induces apoptosis in human Jurkat T cells overexpressing Bcl-2 and also in all human prostate, breast, tongue and brain tumor cell lines we have tested to date, without exception. In contrast, etoposide, a standard anticancer drug, fails to kill these cells when employed under the same conditions. The apoptosis-inducing abilities of CEP1612 and its analogous compounds match precisely their order for inhibition of the proteasome chymotrypsin-like activity. CEP1612-induced apoptosis is p53-independent, inhibitable by a tetrapeptide caspase inhibitor, and associated with accumulation of the cyclin-dependent kinase inhibitors p21 and p27. Furthermore, CEP1612 selectively accumulates p27 and induces apoptosis in simian virus 40-transformed, but not the parental normal, human fibroblasts. Proteasome inhibitors such as those investigated herein might therefore have potential use as novel anticancer drugs.
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PMID:Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts. 989 13

Apoptosis is a mechanism of cell death that occurs in normal development and on the regulation of vertebrate tissues and organ cellularity. Neurons undergo p53-dependent and p53-independent apoptosis, depending upon the stimulus that triggers DNA fragmentation. Many neurons in the developing nervous system suffer apoptosis, with the cyclin D1 being an essential mediator of neuronal cell death. Other characteristics of apoptosis are: condensation of the nucleus, fragmentation of chromatin at nucleosome linkage sites, membrane blebbing, and the formation of apoptotic bodies. Among the possible molecular mechanisms are: (a) activation of proteases, as ICE (Il-1 beta converting enzyme); (b) calpain is activated in several cells, with PARP (Poly-ADP-ribose polymerase) and a small U1 Ribonucleoprotein, being substrates for ICE and its homologs such as ICH and others proteins. The p53 gene encodes a transcription factor that contributes to several different cellular activities, including apoptosis, the cellular response to radiation, and the activation of proteins such as GADD, Bcl-2 (represses to apoptosis) and Bax. P53 exerts a role as inductor of apoptosis by transactivating expression of the Bax gene. The p53 gene tumor suppressor limits cellular proliferation by including either the arrest of cell cycle in G1, or apoptosis, depending on the cellular context. The p21 is an inhibitor of cyclin-dependent kinase, which is transactivated by p53. During apoptosis, there is an activation of both, c-myc, and the transcription factor NF-kB, which is a important regulator of apoptosis. As an example of signalization of apoptosis we have selected to illustrate the problem related to the system Fas/APO in thymocytes.
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PMID:[Molecular bases of the programmed cell death process: implications of tumor suppressor protein p53 and other proteins in the control of cell cycle. Mechanisms of apoptotic action. Review]. 992 5

The purpose of the present study was to study the mechanisms involved in the induction of apoptosis and by tributyltin (TBT) in rainbow trout hepatocytes, and to examine the role of intracellular Ca2+, protein kinase C (PKC) and proteases in the apoptotic process. The intracellular Ca2+ chelator BAPTA-AM has a suppressive effect on TBT-mediated apoptosis. However, exposure to the ionophore A23187 is not sufficient to induce apoptosis in trout hepatocytes. The results obtained also show that TBT stimulates PKC gamma and delta translocation from cytosol to the plasma membrane in trout hepatocytes after 30 min of exposure. However, PKC gamma translocation is down-regulated after 90 min of treatment. The addition of protein kinase inhibitors (staurosporine and H-7) not only fails to inhibit apoptosis induced by TBT, but also leads to enhancement of DNA fragmentation. These inhibitors also afford a remarkable protection against the loss of plasma membrane integrity caused by TBT exposure. PMA, a direct activator of PKC, fails to stimulate DNA fragmentation. In addition, Z-VAD.FMK is an extremely potent inhibitor of TBT-induced apoptosis in trout hepatocytes, indicating that the activation of ICE-like proteases is a key event in this process. The cysteine protease inhibitor N-ethylmaleimide also prevented TBT-induced DNA fragmentation. Taken together, these data allow for the first time to suggest a mechanistic model of TBT-induced apoptosis. We propose that TBT could trigger apoptosis through a step involving Ca2+ efflux from the endoplasmic reticulum or other intracellular pools and by mechanisms involving cysteine proteases, such as calpains, as well as the phosphorylation status of apoptotic proteins such as Bcl-2 homologues.
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PMID:Tributyltin triggers apoptosis in trout hepatocytes: the role of Ca2+, protein kinase C and proteases. 999 Feb 99

The Bcl-2 protein has an anti-apoptotic effect in neuronal and other cell types. We show for the first time that the Bcl-2 promoter is activated by the neuronal survival factor nerve growth factor (NGF) and that this effect is dependent on a region of the promoter from -1472 to -1414. This activation requires the Rap-1 G protein and the MEK-1 and p42/p44 MAPK enzymes but is independent of other NGF-activated signalling pathways involving protein kinase A or protein kinase C.
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PMID:Activation of the Bcl-2 promoter by nerve growth factor is mediated by the p42/p44 MAPK cascade. 1021 80

This is the first report demonstrating that NIH/3T3 fibroblasts utilize the Raf-1/MAPK pathway to sensitize themselves to tumor necrosis factor-alpha (TNF-alpha) cytotoxicity under Ha-rasVal12 oncogene-overexpressed conditions. This paper clearly shows that the sensitivity of NIH/3T3 cells to TNF-alpha cytotoxicity positively correlated with the expression level of activated Ha-ras transgene, which was manipulated either positively by isopropyl-beta-d-thiogalactoside (IPTG) induction or negatively by a ribozyme or a dominant negative Ras suppression. Further analysis revealed that after TNF-alpha treatment, Ha-ras-overexpressed transformants underwent apoptosis. Overexpression of dominant negative Raf-1, Rac1, or RhoA in the Ha-ras transformants clarified that among these factors, only dominant negative Raf-1 could reverse the cell sensitivity to TNF-alpha, indicating that Raf-1, as a proapoptotic factor, indeed participates in TNF-alpha cytotoxicity. The anti-apoptotic roles of Bcl-2 and PI(3) kinase are also demonstrated by the Ha-ras transformants which became more resistant to TNF-alpha while overexpressing Bcl-2 or the activated p110 catalytic subunit. The analyses of the cell cycle and nuclear transcription factor activities revealed that TNF-alpha treatment caused the Ha-ras overexpressed transformants to shift from S to G0/G1 phase and increased the responses of AP-1, c-fos, and c-myc. Taken together, we suggest that the possible action of Ha-ras overexpression to sensitize TNF-alpha-treated fibroblasts is predominantly through the Ras/Raf-1/MAPK pathway to increase the responses of AP-1, c-fos, and c-myc, which are possibly involved in the aberration of cell cycle machinery, and subsequently to turn on the death program.
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PMID:Selective activation of Ha-ras(val12) oncogene increases susceptibilityof NIH/3T3 cells to TNF-alpha. 1022 51


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