Oncogenic ras and p53 cooperate to induce cellular senescence
Oncogenic ras and p53 cooperate to induce cellular senescence
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DOI：
10.1128/mcb.22.10.3497-3508.2002
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发表时间：
2002-05-01
影响因子：
5.3
通讯作者：
Lowe, SW
中科院分区：
文献类型：
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作者：
Ferbeyre, G;de Stanchina, E;Lowe, SW
鼠成纤维细胞中丝裂原活化蛋白（MAP）激酶级联的致癌激活启动依赖于ARF/p53肿瘤抑制途径的衰老样细胞周期停滞为了研究p53是否足以诱导衰老，我们将条件性鼠p53等位基因（p53（val 135））引入p53缺失的小鼠胚胎成纤维细胞中，并在表达p53、致癌Ras或这两种基因产物的细胞中检测细胞增殖和衰老。有条件的p53激活有效地诱导可逆的细胞周期停滞，但不能诱导衰老的功能。与此相反，致癌ras或激活的mek 1与p53的共表达增强p53的水平和活性相对于单独观察到的p53，并产生不可逆的细胞周期停滞，显示细胞衰老的功能。p19（ARF）是这种效应所必需的，因为p53（-/-）ARF（-/-）双无效细胞在致癌Ras和p53共表达后不能经历衰老。虽然在ARF-null细胞中获得的外源性p53水平相对较低，但p19（ARF）对p53的稳定作用不能解释致癌Ras和p53在促进衰老中的协同作用。因此，在p53（-/-）mdm 2（-/-）双无效细胞中，无致癌ras的p53表达增强产生极高的p53水平，但不诱导衰老。总之，我们的研究结果表明，致癌激活的MAP激酶途径在鼠成纤维细胞转化为衰老诱导剂p53通过定量和定性的机制。
Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the ARF/p53 tumor suppressor pathway. To investigate whether p53 is sufficient to induce senescence, we introduced a conditional murine p53 allele (p53(val135)) into p53-null mouse embryonic fibroblasts and examined cell proliferation and senescence in cells expressing p53, oncogenic Ras, or both gene products. Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53 levels and activity relative to that observed for p53 alone and produced an irreversible cell cycle arrest that displayed features of cellular senescence. p19(ARF) was required for this effect, since p53(-/-) ARF(-/-) double-null cells were unable to undergo senescence following coexpression of oncogenic Ras and p53. Although the levels of exogenous p53 achieved in ARF-null cells were relatively low, the stabilizing effects of p19(ARF) on p53 could not explain the cooperation between oncogenic Ras and p53 in promoting senescence. Hence, enforced p53 expression without oncogenic ras in p53(-/-) mdm2(-/-) double-null cells produced extremely high p53 levels but did not induce senescence. Taken together, our results indicate that oncogenic activation of the MAP kinase pathway in murine fibroblasts converts p53 into a senescence inducer through both quantitative and qualitative mechanisms.