Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway
Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway
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DOI：
10.1046/j.1365-2443.2003.00620.x
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发表时间：
2003-02-01
期刊：
影响因子：
2.1
通讯作者：
Ishikawa, F
中科院分区：
文献类型：
--
作者：
Iwasa, H;Han, JH;Ishikawa, F
背景资料：细胞衰老是正常细胞所表现出的不可逆的生长停滞状态，并且在由端粒缩短引起的复制性衰老中已被最广泛地研究。一些条件，包括致癌Ras过度表达和不适当的培养条件，也诱导衰老而不缩短端粒。然而，目前还不清楚一组常见的衰老表型是如何在各种类型的senescenceResults诱导：我们证明，p38丝裂原活化蛋白激酶（MAPK）在衰老细胞端粒缩短，Ras-Raf激活，氧化应激或不适当的培养条件下起着重要的致病作用。通过监测p38激活的动力学，我们认为p38不是直接由初始刺激激活的，而是响应于由这些刺激引起的未识别的细胞条件。重要的是，这种p38激活条件似乎被定量地定义为连续和低水平应力的总和，并且即使在初始刺激被撤回后仍然存在，这可以解释众所周知的细胞衰老的不可逆性。我们还发现，乳头瘤病毒E7能消除p38诱导的生长停滞，但不能消除其他衰老相关的表型，表明pRb在p38下游的不同作用。结论：这些结果表明，p38包含响应不同刺激的衰老执行途径。
Background: Cellular senescence is a state of irreversible growth arrest shown by normal cells, and has been most extensively studied in replicative senescence caused by telomere shortening. Several conditions, including oncogenic Ras over-expression and inappropriate culture conditions, also induce senescence without telomere shortening. However, it remains unclear how a common set of senescence phenotypes is indistinguishably induced in various types of senescenceResults: We demonstrate that p38 mitogen-activated protein kinase (MAPK) plays important causative roles in senescent cells following telomere shortening, Ras-Raf activation, oxidative stress or inappropriate culture conditions. By monitoring the kinetics of p38 activation, we suggest that p38 is activated not directly by the initial stimuli, but in response to unidentified cellular conditions caused by these stimuli. Importantly, this p38-activating condition appears to be defined quantitatively as a sum of continuous and low-level stresses, and remains even after the initial stimuli are withdrawn, which may explain the well-known irreversible nature of cellular senescence. We also show that papilloma virus E7 abolishes the p38-induced growth arrest but not other senescence-associated phenotypes, indicating the differential role of pRb in the downstream of p38.Conclusion: These results indicate that p38 comprises the senescence-executing pathway in response to diverse stimuli.