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Vol. 18, Issue 11, 4543-4552, November 2007

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

Kwang Seok Kim^*,,, Young Bae Seu, Suk-Hwan Baek^*,, Mi Jin Kim^,, Keuk Jun Kim^,, Jung Hye Kim^*, and Jae-Ryong Kim^*,

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

Submitted March 27, 2007; Revised August 21, 2007; Accepted August 29, 2007
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 micro-RNA 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 -galactosidase (SA--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--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.

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

Abbreviations used: GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HUVEC, human umbilical vein endothelial cell; HDF, human dermal fibroblast; IGF, insulin-like growth factor; IGFBP-5, IGF-binding protein-5; PD, population doublings; SA--gal, senescence-associated -galactosidase.