Abstract
The viability of vertebrate cells depends on survival factors which activate signal transduction pathways that suppress apoptosis. Defects in anti-apoptotic signalling pathways are implicated in many pathologies including cancer, in which apoptosis induced by deregulated oncogenes must be forestalled for a tumour to become established. Phosphatidylinositol-3-kinase (PI(3)K) is involved in the intracellular signal transduction of many receptors and has been implicated in the transduction of survival signals in neuronal cells. We therefore examined the role of PI(3)K, its upstream effector Ras, and its putative downstream protein kinase effectors PKB/Akt and p70S6K (ref. 5) in the modulation of apoptosis induced in fibroblasts by the oncoprotein c-Myc. Here we show that Ras activation of PI(3)K suppresses c-Myc-induced apoptosis through the activation of PKB/Akt but not p70S6K. However, we also found that Ras is an effective promoter of apoptosis, through the Raf pathway. Thus Ras activates contradictory intracellular pathways that modulate cell viability. Induction of apoptosis by Ras may be an important factor in limiting the expansion of somatic cells that sustain oncogenic ras mutations.
MeSH terms
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Androstadienes / pharmacology
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Animals
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Apoptosis* / drug effects
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Cell Line
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Chromones / pharmacology
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Enzyme Inhibitors / pharmacology
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Fibroblasts
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Phosphotransferases (Alcohol Group Acceptor) / metabolism*
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Point Mutation
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Polyenes / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-myc / antagonists & inhibitors
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Proto-Oncogene Proteins c-myc / physiology*
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Rats
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Ribosomal Protein S6 Kinases
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Signal Transduction*
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Sirolimus
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Tamoxifen / analogs & derivatives
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Tamoxifen / pharmacology
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Wortmannin
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ras Proteins / metabolism*
Substances
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Androstadienes
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Chromones
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Enzyme Inhibitors
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Morpholines
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Polyenes
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myc
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Tamoxifen
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afimoxifene
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Phosphotransferases (Alcohol Group Acceptor)
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases
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ras Proteins
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Sirolimus
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Wortmannin