Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway.
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.
Miyauchi
Hideyuki
H
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan.
Minamino
Tohru
T
Tateno
Kaoru
K
Kunieda
Takeshige
T
Toko
Haruhiro
H
Komuro
Issei
I
D001011:Aorta / Q000166:cytology; D001158:Arteries / Q000473:pathology; D015153:Blotting, Western; D001940:Breast / Q000098:blood supply; D002460:Cell Line; D016922:Cellular Senescence; D003331:Coronary Vessels / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D004730:Endothelium, Vascular / Q000166:cytology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007328:Insulin; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D013482:Superoxide Dismutase; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt