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MBC in Press, published online ahead of print September 5, 2007
Mol. Biol. Cell 10.1091/mbc.E07-03-0280

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Submitted on March 27, 2007
Revised on August 21, 2007
Accepted on August 29, 2007

Induction of Cellular Senescence by Insulin-like Growth Factor Binding Protein-5 through a p53-dependent Mechanism

Kwang Seok Kim,*{dagger}{ddagger} Young Bae Seu,{ddagger} Suk-Hwan Baek,*{dagger} Mi Jin Kim,{dagger}{sect} Keuk Jun Kim,{dagger}{sect} Jung Hye Kim,* and Jae-Ryong Kim*{dagger}

*Department of Biochemistry and Molecular Biology, {dagger}Aging-associated Vascular Disease Research Center, and {sect}Department of Pathology, College of Medicine, Yeungnam University, Daegu 705-717, Republic of Korea; {ddagger}Department of Microbiology, College of Natural Science, Kyungpook National University, Daegu 702-701, Republic of Korea

Monitoring Editor: Carl-Henrik Heldin

The insulin-like growth factor (IGF) signaling pathway plays a crucial role in the regulation of cell growth, differentiation, apoptosis and aging. IGF binding proteins (IGFBPs) are important members of the IGF axis. IGFBP-5 is up-regulated during cellular senescence in human dermal fibroblasts and endothelial cells, but the function of IGFBP-5 in cellular senescence is unknown. Here we show that IGFBP-5 plays important roles in the regulation of cellular senescence. Knockdown of IGFBP-5 in old human umbilical endothelial cells (HUVECs) with IGFBP-5 microRNA lentivirus caused partial reduction of a variety of senescent phenotypes, such as changes in cell morphology, increases in cell proliferation and decreases in senescence-associated {beta}-galactosidase (SA-{beta}-gal) staining. In addition, treatment with IGFBP-5 protein or up-regulation of IGFBP-5 in young cells accelerates cellular senescence, as confirmed by cell proliferation and SA-{beta}-gal staining. Premature senescence induced by IGFBP-5 up-regulation in young cells was rescued by knockdown of p53, but not by knockdown of p16. Furthermore, atherosclerotic arteries exhibited strong IGFBP-5-positive staining along intimal plaques. These results suggest that IGFBP-5 plays a role in the regulation of cellular senescence via a p53-dependent pathway and in aging-associated vascular diseases. Keywords: cell aging, IGFBP-5, p53, endothelial cells, atherosclerosis

Address correspondence to: Jae-Ryong Kim (kimjr{at}ynu.ac.kr)






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