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)

Normal and activated Ras proteins are known to act as signal transducers, mediating mitogenic responses. Interactions of p21ras and protein kinase C (PKC) are required in a number of mitogenic or activation signaling pathways. The constitutive expression of activated v-Haras in Jurkat cells, a human T lymphoblastoid cell line, renders the cells susceptible to apoptosis during transient down-regulation or inhibition of PKC. Similarly, the expression of v-Ki-ras in murine fibroblasts induces apoptosis during suppression of PKC activity. This Ras-specific cell death is dependent upon suppression of cellular PKC activity, and can be blocked by the survival-promoting bcl-2 gene product. In vivo phosphorylation studies indicate that Bcl-2 is a phosphoprotein, and the phosphorylation state of Bcl-2 is modulated in the setting of activated p21Ha-ras in response to inhibition of PKC. These findings suggest an interactive regulation of growth or apoptosis in cells which involves at least three molecules: p21ras, PKC and Bcl-2.
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PMID:Direction of p21ras-generated signals towards cell growth or apoptosis is determined by protein kinase C and Bcl-2. 747 73

Mad is a bHLH/Zip protein that, as a heterodimer with Max, can repress Myc-induced transcriptional transactivation. Expression of Mad is induced upon terminal differentiation of several cell types, where it has been postulated to down-regulate Myc-induced genes that drive cell proliferation. Here we show that Mad also blocks transformation of primary rat embryo fibroblasts by c-Myc and the activated c-Ha-Ras oncoproteins. Mad mutants lacking either the basic region, the leucine zipper, or an intact NH2-terminal protein interaction domain fail to inhibit Myc-Ras cotransformation. These results indicate that the repression of cotransformation requires DNA-binding and is mediated by multiple protein-protein interactions involving both Max and mSin3, a putative mammalian corepressor protein. With increasing amounts of the cotransfected myc gene, the numbers of transformed foci are reduced and the ability of Mad to inhibit focus formation is attenuated. Moreover, cell lines derived from such foci constitutively express both Myc and Mad proteins. Whereas Bcl-2 can significantly increase the numbers of transformed foci by enhancing the survival of myc-ras-transfected cells, it does not counteract the repressive effects of Mad on transformation, suggesting that Mad affects the growth properties rather than the viability of cells. Taken together, our results demonstrate that Mad is capable of antagonizing the biological effects of Myc and thereby suggest that Mad could function as a tumor suppressor gene.
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PMID:Repression of Myc-Ras cotransformation by Mad is mediated by multiple protein-protein interactions. 766 17

A variant of human prostate PC3 cells, isolated from PC3 cells, was shown to be significantly resistant (> 10-fold) to several clinically active anticancer drugs, including VP-16 and cisplatin. Previous studies showed that resistance to these drugs was not due to expression of the mdr1 gene, or modifications in topoisomerases but may have resulted from high expressions of certain proto-oncogenes (Yamazaki et al. (1994) Biochim. Biophys. Acta 1226, 89-96). Flow cytometry, DNA gel electrophoresis and northern blot analysis were used to further characterize drug responses in sensitive and resistant cells. Treatment of the sensitive PC3 cells with VP-16 and CDDP resulted in accumulation of cells in S and G2, and G1 and S phases, respectively, and caused significant degradation of the genomic DNA into internucleosomal sized DNA fragments, indicating apoptosis. In contrast, resistant PC3 cells showed little or no DNA fragmentation. Resistant PC3(R) cells expressed 2-3-fold more bcl2 protein than the parental PC3 cells, and overexpressed c-myc, c-jun and H-ras mRNA compared to sensitive cells. Treatment with VP-16 or CDDP significantly induced c-myc mRNA levels in sensitive PC3 cells. H-ras message was not affected by either VP-16 or CDDP treatment in PC3 cells. These studies, taken together, suggest that a differential susceptibility to apoptosis and chemosensitivity may be related to altered levels of bcl2 and/or oncogene overexpression in PC3(R) cells.
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PMID:Relationships between proto-oncogene expression and apoptosis induced by anticancer drugs in human prostate tumor cells. 782 30

Ras proteins are members of a superfamily of small GTPases that are involved in many aspects of cell growth control. The ras p21 protooncogene products, H-ras, K-ras, and N-ras, transmit signals from growth factor receptors to a cascade of protein kinases that begins with the Raf protooncogene product, and leads to alterations in transcription factors and cell cycle proteins in the nucleus. This cascade is controlled at several points: Ras p21 proteins are regulated by GAPs and by exchange factors, whose activities are altered by growth factor receptor activation (Boguski and McCormick, 1993: Nature 366:643-654). Transmission of signals from Ras to Raf is regulated by the Ras-related protein Rap1 (a protein capable of reverting cell transformation) and by cAMP. Other aspects of Ras p21 regulation will be discussed, including the existence of RasGDl proteins that inhibit GDP dissociation from Ras, and may thus regulate the level of active Ras in the cell. The role of Ras in activation of Raf kinase appears to be limited to the recruitment of Raf to the plasma membrane, at which time Raf becomes stably modified to render it active (Leevers et al., 1994: Nature 369:411-414; Stokoe et al., 1994: Science 264:1463-1467). The nature of these modifications is unclear. Raf in the plasma membrane becomes associated with insoluble structural cell components that may be part of the activation. Furthermore, Raf is associated with proteins of the 14-3-3 family that appear necessary for kinase activation. The 14-3-3 proteins interact with all three conserved regions of Raf, including the kinase domain. In addition to Raf, Ras proteins interact with two known classes of proteins in a manner consistent with effector functions: these are the GAPs and regulators of the Ras-related protein Ral referred to as RalGDS. These biochemical data suggest that other functional pathways are regulated by Ras, including, perhaps, pathways involved in regulating cell shape and motility. The protein R-Ras p21 is about 50% identical to the Ras p21 protooncogene product. This protein is incapable of transforming cells, even though it interacts with Raf and other putative Ras effectors (Fernandez-Sarabia and Bischoff, 1993: Nature 366:274-275). On the other hand, it has recently been shown that R-Ras binds to the protooncogene product Bcl-2, a protein that transforms B cells by blocking apoptosis. R-Ras is regulated by the same GAP molecules as H-Ras and the other Ras protooncogene products, and may therefore be activated in a manner co-ordinate with these growth-promoting proteins. The possible connection between R-Ras and apoptosis will be discussed.
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PMID:Ras-related proteins in signal transduction and growth control. 860 82

Cellular oncogenes have been shown to play crucial roles in the cell death process induced by cytotoxic agents. In this study, we have demonstrated that v-H-ras transformed NIH 3T3 cells but not other transformants (v-raf, v-src, v-erbB-2, v-fes and v-mos) exhibited a survival advantage to treatment by a DNA-damaging agent, methylmethanesulfonate (MMS). Subsequently, the biochemical and morphologic criteria of MMS-treated cells were examined. It was found that MMS induced v-H-ras transformants to go through necrosis, but it induced other transformed cells to undergo apoptosis. The levels of glutathione (GSH) within each transformant as well as in NIH 3T3 cells, were determined. The results showed that GSH levels within ras transformants were 2- to 7-fold higher than the levels in other transformants and normal NIH 3T3 cells. By using the GSH synthesis inhibitor buthionine sulfoximine, GSH levels were artificially reduced. This depletion, however, made ras transformed cells more sensitive to MMS killing, but the mode of cell death was still necrosis. Western blot analysis demonstrated that the anti-apoptotic protein Bcl-2 was constitutively expressed in ras transformed cells but not in NIH 3T3 or other transformed cells. The level of Bcl-2 was correlated with the resistant phenotype of ras transformants during MMS treatment. These observations suggest that GSH and Bcl-2 levels may cooperatively confer the resistant phenotype of ras transformants in response to MMS. In addition, the mode of cell death may possibly be determined at least in part by Bcl-2 protein.
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PMID:Differential induction of apoptosis in oncogene-transformed NIH 3T3 cells by methylmethanesulfonate. 868 3

There is increasing evidence that cell cycle transit is potentially lethal, with survival depending on the activation of metabolic pathways which block apoptosis. However, the identities of those pathways coupling cell cycle transit to survival remain undefined. Here we show that the eukaryotic translation initiation factor 4E (eIF4E) can mediate both proliferative and survival signaling. Overexpression of eIF4E completely substituted for serum or individual growth factors in preserving the viability of established NIH 3T3 fibroblasts. An eIF4E mutant (Ser-53 changed to Ala) defective in mediating its growth-factor-regulated functions was also defective in its survival signaling. Survival signaling by enforced expression of eIF4E did not result from autocrine release of survival factors, nor did it lead to increased expression of the apoptosis antagonists Bcl-2 and Bcl-XL. In addition, the execution apparatus of the apoptotic response in eIF4E-overexpressing cells was found to be intact. Increased expression of eIF4E was sufficient to inhibit apoptosis in serum-restricted primary fibroblasts with enforced expression of Myc. In contrast, activation of Ha-Ras, which is required for eIF4E proliferative signaling, did not suppress Myc-induced apoptosis. These data suggest that the eIF4E-activated pathways leading to survival and cell cycle progression are distinct. This dual signaling of proliferation and survival might be the basis for the potency of eIF4E as an inducer of neoplastic transformation.
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PMID:Translational control of programmed cell death: eukaryotic translation initiation factor 4E blocks apoptosis in growth-factor-restricted fibroblasts with physiologically expressed or deregulated Myc. 888 86

The CHST8 mouse hepatocyte cell line, conditionally immortalized with the temperature-sensitive SV40 large T antigen gene, rapidly proliferates at 33 degrees C with active expression of the c-myc proto-oncogene but, due to the heat-labile nature of the mutant T antigens, becomes growth arrested and morphologically senescent at 39 degrees C; this is accompanied by the disappearance of c-myc transcripts. In a previous study, we transfected the CHST8 cells at 33 degrees C with an activated c-H-ras or a c-myc, both of which are frequently involved in mouse hepatocarcinogenesis in vivo. When the temperature was shifted to 39 degrees C, cells with only one of the exogenous oncogenes did not escape from the senescence, but those containing both exhibited an immortal phenotype. In the present study, using this in vitro model of hepatocarcinogenesis, we demonstrated that phenobarbital, a tumor promoter of rodent hepatocarcinogenesis, triggers remarkable apoptosis specifically in the c-myc-transfected CHST8 cells at 39 degrees C, which show abundant c-myc expression despite growth arrest. Dissociation of p53 proteins from degrading T antigens followed by a phenobarbital and c-myc-dependent, 15-fold induction of Bax protein, known to activate the apoptotic pathway downstream of p53, occurred in association with this phenomenon. The effects of phenobarbital and c-myc in increasing Bax on shifting the temperature from 33 degrees C to 39 degrees C were additive, with both having similar degrees of influence on the protein level. Interestingly, subsequent introduction of an activated c-H-ras oncogene into the c-myc-transfected CHST8 cells resulted not only in escape from the growth arrest at 39 degrees C but also in complete inhibition of the phenobarbital-inducible apoptosis along with de novo induction of the Bax antagonist, Bcl-2. These findings strongly suggest that the phenobarbital-inducible apoptosis is mediated by Bax. Although it is a common notion that phenobarbital promotes liver tumor development through suppression of apoptosis, our results, together with the known fact that phenobarbital occasionally inhibits hepatocarcinogenesis in mice, indicate a problematic complexity in its biological activities.
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PMID:Phenobarbital causes apoptosis in conditionally immortalized mouse hepatocytes depending on deregulated c-myc expression: characterization of an unexpected effect. 923 Jan 98

Two human herpesviruses, HHV-6 and HHV-7, recently identified and closely related, were studied for their influence on cellular apoptosis and proliferation. Infection was monitored by viral DNA--and antigen expression. Apoptosis and cell proliferation were determined by immunocytological techniques and the markers p53, p21WAF/Cip, Bax, Bak, Bcl-2, cyclin D1 and PCNA, and also screened for signal transduction indicators such as c-H-ras, c-fos and raf-1. Cell differentiation and function was monitored by determining cell membrane receptors including Fas and CD specificities, and by ELISA tests for interleukin production. Both HHV-6 and HHV-7 readily infected their target cells, yet virus antigen expression and virus replication were less active in HHV-7 infection. Both viruses also induced GM-CFS production. Cell differentiation in terms of CD receptor expression was more pronounced in HHV-6 than in HHV-7 infection. No differences were found in the activity of signal transduction factors. There were quantitative differences in the activation of p53, Bax, p21WAF and Bcl-2 in HHV 6-infected CBC as compared to HHV-7 infection supporting the apoptosis cycle. CyclinD1 activity remained at lower levels in HHV-7 infected CBC, yet was high in similarly infected transformed SupT1 cells. In contrast, HHV-6 supported rather the p53/p21WAF apoptosis pathway in both untransformed CBC and transformed HSB1 cells. Both herpesviruses, HHV-6 and HHV-7, thus possessed similar biological activities in cultures of non-transformed susceptible cells, although with certain quantitative differences. The data reported here may further support the notion that HHV-7 is less active in inducing apoptosis thus favoring continued cell proliferation. The mechanism by which these viruses interfere with the network control of cell proliferation, differentiation and apoptosis appear more complicated than shown here and therefore afford a more detailed study, including a more sensitive technology than immunohistology.
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PMID:In vitro cytobiological effects of human herpesviruses 6 and 7: immunohistological monitoring of apoptosis, differentiation and cell proliferation. 949 80

The phosphatidylinositol 3-kinase (PI3K)-signaling pathway has emerged as an important component of cytokine-mediated survival of hemopoietic cells. Recently, the protein kinase PKB/akt (referred to here as PKB) has been identified as a downstream target of PI3K necessary for survival. PKB has also been implicated in the phosphorylation of Bad, potentially linking the survival effects of cytokines with the Bcl-2 family. We have shown that granulocyte/macrophage colony-stimulating factor (GM-CSF) maintains survival in the absence of PI3K activity, and we now show that when PKB activation is also completely blocked, GM-CSF is still able to stimulate phosphorylation of Bad. Interleukin 3 (IL-3), on the other hand, requires PI3K for survival, and blocking PI3K partially inhibited Bad phosphorylation. IL-4, unique among the cytokines in that it lacks the ability to activate the p21ras-mitogen-activated protein kinase (MAPK) cascade, was found to activate PKB and promote cell survival, but it did not stimulate Bad phosphorylation. Finally, although our data suggest that the MAPK pathway is not required for inhibition of apoptosis, we provide evidence that phosphorylation of Bad may be occurring via a MAPK/ERK kinase (MEK)-dependent pathway. Together, these results demonstrate that although PI3K may contribute to phosphorylation of Bad in some instances, there is at least one other PI3K-independent pathway involved, possibly via activation of MEK. Our data also suggest that although phosphorylation of Bad may be one means by which cytokines can inhibit apoptosis, it may be neither sufficient nor necessary for the survival effect.
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PMID:Dissociation of cytokine-induced phosphorylation of Bad and activation of PKB/akt: involvement of MEK upstream of Bad phosphorylation. 963 68

To examine the biochemical pathways by which activated Ha-Ras(G12V) (Ha-RasV12) induces factor-independent growth of myeloid cells, Ha-Ras effector loop mutations, including Y40C, T35S, and E37G, were analysed in a mouse factor-dependent myeloid cell line, WT19. Expression of a single effector loop mutant, Ha-Ras(G12V, Y40C) (Ha-RasV12C40), inhibited factor-withdrawal apoptosis, suggesting that activation of the phosphatidylinositol 3'-kinase (Pl3K) pathway is essential to prevent cell death. Neither Ha-Ras (G12V, T35S) (Ha-RasV12S35), which activates the Rafl signaling pathway, nor Ha-Ras(G12V, E37G) (Ha-RasV12G37), which stimulates the RalGDS pathway, did not have significant effects on factor-withdrawal apoptosis of myeloid cells. Although Ha-RasV12C40 inhibited apoptosis, it did not stimulate entry into the cell cycle. Cell lines containing the combination of Ha-RasV12G37 and Ha-RasV12C40 were capable of factor-independent cell growth, while expression of the other combinations of the Ha-Ras effector mutants were not. The combined expression of Bcl-2 and Ha-RasV12G37 was not sufficient to stimulate factor independent growth, suggesting that Ha-RasV12C40 activates additional signals, besides blocking apoptosis, which are critical for factor-independent growth of myeloid cells. In factor-starved myeloid cells, inducible expression of Ha-RasV12G37 results in decreased level of p27Kip1 protein, a cyclin-dependent kinase inhibitor (CKI). These data suggest that the factor-independent growth of myeloid cells requires the activation of at least two pathways, one inhibiting factor-withdrawal apoptosis, and another causing cell cycle progression.
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PMID:Regulation of myeloid cell growth by distinct effectors of Ras. 984 Sep 34


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