Insulin-like growth factor (IGF)-I regulates IGF-binding protein-5 gene expression through the phosphatidylinositol 3-kinase, protein kinase B/Akt, and p70 S6 kinase signaling pathway

作     者：Duan, CM Liimatta, MB Bottum, OL 

作者机构：Univ Michigan Dept Biol Ann Arbor MI 48109 USA 

出 版 物：《JOURNAL OF BIOLOGICAL CHEMISTRY》 (生物化学杂志)

年 卷 期：1999年第274卷第52期

页      面：37147-37153页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

基　　金：NIDDK NIH HHS [5P60DK-20572] Funding Source: Medline 

主　　题：细胞 培养的 基因表达调控/药物作用 胰岛素样生长因子结合蛋白质5/遗传学 胰岛素样生长因子Ⅰ/药理学 肌 平滑 血管/细胞学 肌 平滑 血管/代谢 磷酸肌醇3-激酶类/生理学 蛋白质丝氨酸苏氨酸激酶 原癌基因蛋白质类/生理学 原癌基因蛋白质c-akt 视网膜母细胞瘤蛋白质/代谢 核糖体蛋白质S6激酶类/生理学 猪 动物 

摘      要：Expression of the insulin-like growth factor-binding protein 5 (IGFBP-5) gene in vascular smooth muscle cells is up-regulated by IGF-I through an IGF-I receptor-mediated mechanism. In this study, we studied the possible involvement of the mitogen-activated protein kinase (MAPK) and PI 3-kinase signaling pathways in mediating IGF-I-regulated IGFBP-5 gene expression. The addition of Des(1-3)IGF-1, an IGF analog with reduced affinity to IGFBPs, resulted in a transient activation of p44 and p42 MAPK. Inhibition of the MAPK activation by PD98059, however, did not affect IGF-I-stimulated IGFBP-5 expression. Des(1-3)IGF-I treatment also strongly activated PI 3-kinase. This activation was probably mediated through IRS-1, because IGF-1 stimulation resulted in a significant increase in IRS-1- but not IRS-2-associated PI 3-kinase activity, This activation occurred within 5 min and was sustained at high levels for over 6 h. Likewise, Des(1-3)IGF-I caused a long lasting activation of PKB/Akt and p70(s6k). When LY294002 and wortmannin, two specific inhibitors of PI 3-kinase, were added with Des(1-3)IGF-I, the IGF-I-regulated IGFBP-5 expression was negated. The addition of rapamycin, which inhibits IGF-I-induced p70(s6k) activation, significantly inhibited IGF-I-regulated IGFBP-5 gene expression, These results suggest that the action of IGF-I on IGFBP-5 gene expression requires the activation of the PI 3-kinase-PKB/Akt-p70(s6k) pathway but not the MAPK pathway in vascular smooth muscle cells.