Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling
Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling
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DOI：
10.1101/gad.12.19.3008
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发表时间：
1998-10-01
影响因子：
10.5
通讯作者：
Lowe, SW
中科院分区：
文献类型：
--
作者：
Lin, AW;Barradas, M;Lowe, SW
致癌PAS部分通过丝裂原活化蛋白激酶(MAPK)级联系统传递有丝分裂信号，将不死的啮齿动物细胞转化为致瘤状态。在原代细胞中，PAS最初是有丝分裂的，但最终会诱导涉及p53和p16(INK4a)肿瘤抑制因子的过早衰老。MEK(MAPK级联中的一种成分)的结构性激活可同时诱导p53和p16，这是RAS诱导的正常人成纤维细胞衰老所必需的。此外，激活的MEK永久阻止原代小鼠成纤维细胞，但迫使缺乏P53或INK4a的细胞不受控制地有丝分裂和转化。正常细胞和永生化细胞对MAPK级联结构激活的完全相反的反应表明，过早衰老是一种故障安全机制，可以限制过度的PAS有丝分裂信号的转化潜力。因此，结构性MAPK信号激活p53和p16作为肿瘤抑制因子。
Oncogenic Pas transforms immortal rodent cells to a tumorigenic state, in part, by constitutively transmitting mitogenic signals through the mitogen-activated protein kinase (MAPK) cascade. In primary cells, Pas is initially mitogenic but eventually induces premature senescence involving the p53 and p16(INK4a) tumor suppressors. Constitutive activation of MEK (a component of the MAPK cascade) induces both p53 and p16, and is required for Ras-induced senescence of normal human fibroblasts. Furthermore, activated MEK permanently arrests primary murine fibroblasts but forces uncontrolled mitogenesis and transformation in cells lacking either p53 or INK4a. The precisely opposite response of normal and immortalized cells to constitutive activation of the MAPK cascade implies that premature senescence acts as a fail-safe mechanism to limit the transforming potential of excessive Pas mitogenic signaling. Consequently, constitutive MAPK signaling activates p53 and p16 as tumor suppressors.