Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway
Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway
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DOI：
10.1038/sj.emboj.7600045
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发表时间：
2004-01-14
期刊：
影响因子：
11.4
通讯作者：
Komuro, I
中科院分区：
文献类型：
--
作者：
Miyauchi, H;Minamino, T;Komuro, I
胰岛素/胰岛素样生长因子-1/磷脂酰肌醇-3激酶/Akt信号通路调节线虫的寿命和抗氧化性。这一调控过程涉及叉头转录因子DAF-16的活性。虽然在从酵母到小鼠的各种生物体中，这一途径各部分的功能缺失突变已被证明可以延长寿命，但已有报道称，Akt的激活可以促进哺乳动物细胞的增殖和存活。在这里，我们发现Akt的活性随着细胞的衰老而增加，抑制Akt可以延长原代培养的人内皮细胞的寿命。Akt的结构性激活通过依赖于p53/p21的途径促进细胞衰老样生长停滞，而Akt对叉头转录因子FOXO3a的抑制是这种生长停滞发生的关键。FOXO3a通过调节活性氧水平影响P53活性。这些发现揭示了Akt在调节细胞寿命方面的新作用，并提示Akt的长寿机制在原代培养的人细胞中是保守的，Akt诱导的衰老可能参与了血管的病理生理。
The signaling pathway of insulin/insulin-like growth factor-1/phosphatidylinositol- 3 kinase/Akt is known to regulate longevity as well as resistance to oxidative stress in the nematode Caenorhabditis elegans. This regulatory process involves the activity of DAF-16, a forkhead transcription factor. Although reduction-of-function mutations in components of this pathway have been shown to extend the lifespan in organisms ranging from yeast to mice, activation of Akt has been reported to promote proliferation and survival of mammalian cells. Here we show that Akt activity increases along with cellular senescence and that inhibition of Akt extends the lifespan of primary cultured human endothelial cells. Constitutive activation of Akt promotes senescence-like arrest of cell growth via a p53/p21-dependent pathway, and inhibition of forkhead transcription factor FOXO3a by Akt is essential for this growth arrest to occur. FOXO3a influences p53 activity by regulating the level of reactive oxygen species. These findings reveal a novel role of Akt in regulating the cellular lifespan and suggest that the mechanism of longevity is conserved in primary cultured human cells and that Akt-induced senescence may be involved in vascular pathophysiology.