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Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21‐dependent pathway
Author(s) -
Miyauchi Hideyuki,
Minamino Tohru,
Tateno Kaoru,
Kunieda Takeshige,
Toko Haruhiro,
Komuro Issei
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600045
Subject(s) - biology , in vitro , microbiology and biotechnology , protein kinase b , pi3k/akt/mtor pathway , phosphorylation , signal transduction , cancer research , genetics
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.