Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB
Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB
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DOI：
10.1038/385544a0
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发表时间：
1997-02-06
期刊：
影响因子：
64.8
通讯作者：
Evan, G
中科院分区：
文献类型：
--
作者：
KauffmanZeh, A;RodriguezViciana, P;Evan, G
脊椎动物细胞的存活依赖于激活抑制细胞凋亡的信号转导通路的生存因子。包括癌症在内的许多病理过程中都涉及到抗凋亡信号通路的缺陷，在这些病理过程中，必须预先阻止癌基因失控诱导的细胞凋亡，才能建立肿瘤。磷脂酰肌醇-3-激酶(PI(3)K)参与多种受体的细胞内信号转导，并参与神经细胞生存信号的转导[1]。因此，我们研究了PI(3)K、其上游效应物RAS(2)和其可能的下游蛋白激酶效应物PKB/Akt(3，4)和p70(S6K)的作用(参考文献)。5)癌蛋白c-Myc对成纤维细胞凋亡的调控作用。在这里，我们发现PI(3)K的RAS激活通过激活PKB/Akt而不是p70(S6K)来抑制c-Myc诱导的细胞凋亡。然而，我们也发现，RAS通过Raf途径有效地促进了细胞的凋亡。因此，RAS激活了调节细胞活力的相互矛盾的细胞内途径。RAS诱导细胞凋亡可能是限制维持ras癌基因突变的体细胞扩张的一个重要因素。
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(1). We therefore examined the role of PI(3)K, its upstream effector Ras(2), and its putative downstream protein kinase effecters PKB/Akt(3,4) and p70(S6K) (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 p70(S6K). 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.