Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway

Hideyuki Miyauchi; Tohru Minamino; Kaoru Tateno; Takeshige Kunieda; Haruhiro Toko; Issei Komuro

doi:10.1038/sj.emboj.7600045

Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway

EMBO J. 2004 Jan 14;23(1):212-20. doi: 10.1038/sj.emboj.7600045. Epub 2004 Jan 8.

Authors

Hideyuki Miyauchi¹, Tohru Minamino, Kaoru Tateno, Takeshige Kunieda, Haruhiro Toko, Issei Komuro

Affiliation

¹ Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aorta / cytology
Arteries / pathology
Blotting, Western
Breast / blood supply
Cell Line
Cellular Senescence*
Coronary Vessels / pathology
Cyclin-Dependent Kinase Inhibitor p21
Cyclins / metabolism*
DNA-Binding Proteins / antagonists & inhibitors
Endothelium, Vascular / cytology
Forkhead Box Protein O1
Forkhead Transcription Factors
Gene Expression Regulation*
Genes, Reporter
Humans
Immunohistochemistry
Insulin / metabolism
Luciferases / metabolism
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-akt
Reactive Oxygen Species / metabolism
Retroviridae / genetics
Signal Transduction*
Superoxide Dismutase / metabolism
Transcription Factors / antagonists & inhibitors
Tumor Suppressor Protein p53 / metabolism*
Umbilical Veins / cytology

Substances

CDKN1A protein, human
Cyclin-Dependent Kinase Inhibitor p21
Cyclins
DNA-Binding Proteins
FOXO1 protein, human
Forkhead Box Protein O1
Forkhead Transcription Factors
Insulin
Proto-Oncogene Proteins
Reactive Oxygen Species
Transcription Factors
Tumor Suppressor Protein p53
Luciferases
Superoxide Dismutase
AKT1 protein, human
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt