Regulation of replicative senescence by insulin-like growth factor-binding protein 3 in human umbilical vein endothelial cells.
Insulin/insulin-like growth factor (IGF) signaling pathways are among the most conserved processes in aging in organisms ranging from yeast to mammals. Previously, using cDNA microarray technology, we reported that expression of IGF-binding protein 3 (IGFBP3), one of the IGF-binding proteins, was increased with age in human dermal fibroblasts. In this study, the role of IGFBP3 on cellular senescence was studied in human umbilical vein endothelial cells (HUVEC). The expression levels of IGFBP3 mRNA and protein were increased in HUVECs with age. Knockdown of IGFBP3 in old cells with IGFBP3 short hairpin RNA (shRNA) retrovirus resulted in the partial reduction of a variety of senescent phenotypes, such as changes in cell morphology, and decreases in population doubling times and senescence-associated beta-galactosidase (SA-beta-gal) staining. Down-regulation of IGFBP3 rescued the growth arrest induced by p53 overexpression in young HUVECs. In contrast, up-regulation of IGFBP3 in young cells and prolonged IGFBP3 treatment accelerated cellular senescence, confirmed by cell proliferation and SA-beta-gal staining. The FOXO3a (forkhead box O3a) protein level was increased in old IGFBP3 shRNA cells. The treatment of young HUVECs with IGFBP3 repressed the levels of FOXO3a protein. Furthermore, calorie restriction reduced IGFBP3 protein levels, which were found to be increased with age in the rat liver and serum. These results suggest that IGFBP3 might play an important role in the cellular senescence of HUVECs as well as in vivo aging.
Kim
Kwang Seok
KS
Department of Biochemistry and Molecular Biology, Aging-associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu, South Korea.
Kim
Min-Sun
MS
Seu
Young Bae
YB
Chung
Hae Young
HY
Kim
Jung Hye
JH
Kim
Jae-Ryong
JR
D000818:Animals; D031204:Caloric Restriction; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D016158:Genes, p53; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics* / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins; D014161:Transduction, Genetic; D014471:Umbilical Veins
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I