MDM2 Regulates Vascular Endothelial Growth Factor mRNA Stabilization in Hypoxia

• Type of Material: Article
• Authors: Sheng Zhou, Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Lubing Gu, Emory University; Jing He, Emory University; Hailong Zhang, Emory University; Muxiang Zhou, Emory University
• Language: English
• Date: 2011-12
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2011, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://mcb.asm.org/content/31/24/4928
• Title of Journal or Parent Work: Molecular and Cellular Biology
• ISSN: 0270-7306
• Volume: 31
• Issue: 24
• Start Page: 4928
• End Page: 4937
• Grant/Funding Information: This work was supported by the National Natural Science Foundation of China (grant 81072168) and the National Institutes of Health of the United States (R01 CA123490).
• Research Categories: Health Sciences, Oncology

Abstract

Expression of vascular endothelial growth factor (VEGF) increases in cancer cells during hypoxia. Herein, we report that the MDM2 oncoprotein plays a role in hypoxia-mediated VEGF upregulation. In studying the characteristics of MDM2 and VEGF expression in neuroblastoma cells, we found that hypoxia induced significantly higher upregulation of both VEGF mRNA and protein in MDM2-positive cells than in the MDM2-negative cells, even in cells without wild-type (wt) p53. We found that hypoxia induced translocation of MDM2 from the nucleus to the cytoplasm, which was associated with increased VEGF expression. Enforcing overexpression of cytoplasmic MDM2 by transfection of the mutant MDM2/166A enhanced expression of VEGF mRNA and protein production, even without hypoxia. The results of mechanistic studies demonstrated that the C-terminal RING domain of the MDM2 protein bound to the AU-rich sequence within the 3′ untranslated region (3′UTR) of VEGF mRNA; this binding increased VEGF mRNA stability and translation. In addition, knockdown of MDM2 by small interfering RNA (siRNA) in MDM2-overexpressing cancer cells resulted in inhibition of VEGF protein production, cancer cell survival, and angiogenesis. Our results suggest that MDM2 plays a p53-independent role in the regulation of VEGF, which may promote tumor growth and metastasis.