Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence.
Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence.
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胰岛素样生长因子 1 调节细胞衰老中的 SIRT1-p53 通路
DOI：
10.1111/acel.12219
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发表时间：
2014-08
期刊：
影响因子：
7.8
通讯作者：
Xiao ZX
中科院分区：
文献类型：
--
作者：
Tran D;Bergholz J;Zhang H;He H;Wang Y;Zhang Y;Li Q;Kirkland JL;Xiao ZX
众所周知，细胞衰老可以阻止衰老和应激细胞的增殖，它对抗癌发展起着关键作用，也与生物衰老密切相关。虽然胰岛素样生长因子(IGF)信号的增加会诱导细胞增殖、存活和癌症进展，但众所周知，IGF信号的中断会在延缓衰老过程的同时延长寿命。IGF信号调节衰老的分子机制以及IGF是否调控细胞衰老的分子机制尚不清楚。在这项研究中，我们证明了IGF-1在促进细胞增殖和细胞衰老方面具有双重功能。虽然急性IGF-1暴露促进细胞增殖，并被P53所反对，但长期的IGF-1治疗以P53依赖的方式诱导细胞提前衰老。我们发现，长时间的IGF-1处理抑制了SIRT1脱乙酰酶的活性，导致P53乙酰化的增加以及P53的稳定和激活，从而导致细胞过早衰老。此外，SIRT1的表达或P53的抑制均可阻止IGF-1诱导的细胞过早衰老。综上所述，这些发现表明，P53在监测IGF-1诱导的增殖和早衰过程中发挥了分子开关的作用，并提示了IGF-1-SIRT1-P53信号在细胞衰老和衰老中可能的分子联系。
Cellular senescence, which is known to halt proliferation of aged and stressed cells, plays a key role against cancer development and is also closely associated with organismal aging. While increased insulin-like growth factor (IGF) signaling induces cell proliferation, survival and cancer progression, disrupted IGF signaling is known to enhance longevity concomitantly with delay in aging processes. The molecular mechanisms involved in the regulation of aging by IGF signaling and whether IGF regulates cellular senescence are still poorly understood. In this study, we demonstrate that IGF-1 exerts a dual function in promoting cell proliferation as well as cellular senescence. While acute IGF-1 exposure promotes cell proliferation and is opposed by p53, prolonged IGF-1 treatment induces premature cellular senescence in a p53-dependent manner. We show that prolonged IGF-1 treatment inhibits SIRT1 deacetylase activity, resulting in increased p53 acetylation as well as p53 stabilization and activation, thus leading to premature cellular senescence. In addition, either expression of SIRT1 or inhibition of p53 prevented IGF-1-induced premature cellular senescence. Together, these findings suggest that p53 acts as a molecular switch in monitoring IGF-1-induced proliferation and premature senescence, and suggest a possible molecular connection involving IGF-1-SIRT1-p53 signaling in cellular senescence and aging.
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影响因子：
3.4
作者：
Ding, Juan;Sackmann-Sala, Lucila;Kopchick, John J.
通讯作者：
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影响因子：
6
作者：
de Ostrovich, Krisztina Kovacs;Lambertz, Isabel;Fuchs-Young, Robin
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影响因子：
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作者：
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Scrable, H
影响因子：
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作者：
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通讯作者：
Pinkas-Kramarski, Ronit
影响因子：
64.5
作者：
LIU, JP;BAKER, J;EFSTRATIADIS, A
通讯作者：
EFSTRATIADIS, A