Cellular response to oncogenic Ras involves induction of the Cdk4 and Cdk6 inhibitor p15INK4b
Cellular response to oncogenic Ras involves induction of the Cdk4 and Cdk6 inhibitor p15INK4b
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DOI：
10.1128/mcb.20.8.2915-2925.2000
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发表时间：
2000-04-01
影响因子：
5.3
通讯作者：
Pellicer, A
中科院分区：
文献类型：
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作者：
Malumbres, M;Perez de Castro, I;Pellicer, A
在某些类型的肿瘤中，细胞周期抑制因子p15(INK4b)经常与p16(INK4a)和p19(ARF)一起被纯合缺失失活，尽管p15(INK4b)的抑癌能力仍然受到质疑，但已发现在没有p16(INK4a)改变的情况下，p15(INK4b)在血液系统恶性肿瘤中被高甲基化特异性失活。我们发现，在体外，p15(INK4b)是一种很强的PAS细胞转化抑制因子。令人惊讶的是，p15(INK4b)在培养细胞中被致癌RAS诱导的程度与p16(INK4a)相似，它们的表达与G(1)过早停滞和衰老有关。RAS依赖的这两个INK4基因的诱导主要由Raf-MEK-Erk途径介导。对激活的和显性的阴性形式的RAS效应器的研究表明，Raf-MEK-Erk通路对于p15(INK4b)和p16(INK4a)启动子的诱导是必不可少的，尽管其他RAS效应器通路可以相互协作，产生更强的反应，但我们的结果表明，p15(INK4b)本身能够阻止RAS和其他癌基因如RGR(RGR)等癌基因的细胞转化。事实上，从p15(INK4b)基因敲除小鼠分离的胚胎成纤维细胞对RAS或RGR癌基因的转化敏感，而野生型胚胎成纤维细胞不容易转化。同样，p15(INK4b)缺陷的小鼠胚胎成纤维细胞比野生型细胞对RGR和E1a癌基因的组合转化更敏感。因此，至少在某些细胞类型中，细胞周期抑制因子p15(INK4b)参与了在细胞内不适当的致癌RAS激活后触发的肿瘤抑制活性。
The cell cycle inhibitor p15(INK4b) is frequently inactivated by homozygous deletion together with p16(INK4a) and p19(ARF) in some types of tumors, Although the tumor suppressor capability of p15(INK4b) is still questioned, it has been found to be specifically inactivated by hypermethylation in hematopoietic malignancies in the absence of p16(INK4a) alterations. Here we show that, in vitro, p15(INK4b) is a strong inhibitor of cellular transformation by pas. Surprisingly, p15(INK4b) is induced in cultured cells by oncogenic Ras to an extent similar to that of p16(INK4a), and their expression is associated with premature G(1) arrest and senescence. Ras-dependent induction of these two INK4 genes is mediated mainly by the Raf-Mek-Erk pathway. Studies with activated and dominant negative forms of Ras effecters indicate that the Raf-Mek-Erk pathway is essential for induction of both the p15(INK4b) and p16(INK4a) promoters, although other Ras effector pathways can collaborate, giving rise to a stronger response, Our results indicate that p15(INK4b), by itself, is able to stop cell transformation by Ras and other oncogenes such as Rgr (a new oncogene member of the Ral-GDS family, whose action is mediated through Ras). In fact, embryonic fibroblasts isolated from p15(INK4b) knockout mice are susceptible to transformation by the Ras or Rgr oncogene whereas wild-type embryonic fibroblasts are not. Similarly, p15(INK4b)-deficient mouse embryo fibroblasts are more sensitive than wild-type cells to transformation by a combination of the Rgr and E1A oncogenes. The cell cycle inhibitor p15(INK4b) is therefore involved, at least in some cell types, in the tumor suppressor activity triggered after inappropriate oncogenic Ras activation in the cell.