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J. Biol. Chem., Vol. 279, Issue 44, 45643-45651, October 29, 2004

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Vascular Endothelial Growth Factor Transcriptional Activation Is Mediated by Hypoxia-inducible Factor 1, HDM2, and p70S6K1 in Response to Phosphatidylinositol 3-Kinase/AKT Signaling^*

Heath D. Skinner, Jenny Z. Zheng, Jing Fang, Faton Agani, and Bing-Hua Jiang¶

From the Mary Babb Randolph Cancer Center, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, West Virginia 26506-9300 and the Department of Anatomy, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

Vascular endothelial growth factor (VEGF) expression is elevated in ovarian and other cancer cells. However, the mechanism that causes the increase in VEGF expression still remains to be elucidated. In this study, we demonstrated that activation of PI3K signaling mediated VEGF protein expression at the transcriptional level through hypoxia-inducible factor 1 (HIF-1) expression in human ovarian cancer cells. We found that inhibition of PI3K activity by LY294002 decreased VEGF transcriptional activation and that forced expression of AKT completely reversed the inhibitory effect. HDM2 and p70S6K1 are two downstream targets of AKT that mediate growth factor-induced VEGF transcriptional activation and HIF-1 expression. The inhibition of PI3K by LY294002 inhibited p70S6K1 and HDM2 activity in the cells. Forced expression of p70S6K1 or HDM2 reversed LY294002-inhibited VEGF transcriptional activation and HIF-1 expression. This study identifies a potential novel mechanism responsible for increased VEGF expression in ovarian cancer cells. It also indicates the important role of VEGF and HIF-1 in ovarian tumorigenesis and angiogenesis, which is mediated by the PI3K/AKT/HDM2 and AKT/p70S6K1 pathways in ovarian cancer cells.

Received for publication, April 13, 2004 , and in revised form, July 26, 2004.

^* This work was supported by National Institutes of Health Grant RR16440 (to B.-H. J.) and NS41309 (to F. A.) and by American Cancer Society Research Scholar Grant 04-076-01-TBE (to B.-H. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Fax: 304-293-4667; E-mail: bhjiang{at}hsc.wvu.edu.

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