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Nutlin3 Blocks Vascular Endothelial Growth Factor Induction by Preventing the Interaction between Hypoxia Inducible Factor 1 and Hdm2

¹ Departments of Radiation Oncology and Pharmacology, Case Comprehensive Cancer Center, Case Western Reserve University, ² Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic Foundation, and Case Comprehensive Cancer Center, Cleveland, Ohio; ³ Department of Microbiology and Immunology, Indiana University School of Medicine, and the Walther Cancer Institute, Indianapolis, Indiana; and ⁴ Department of Surgery, University of California San Francisco, San Francisco, California

Requests for reprints: Lindsey D. Mayo, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202. Phone: 317-278-3173; Fax: 317-278-5413.

Hdm2 is elevated in numerous types of malignancies and is thought to impede the function of wild-type p53. Reactivation of p53 by disrupting the association with Hdm2 was the impetus for the development of Nutlin3. Although regulation of p53 has been the central focus of Hdm2 activity, it also binds other proteins through its p53-binding domain. Here, we show that hypoxia-inducible factor 1 (HIF1) binds to Hdm2 in the domain designated to bind p53. HIF1 and p53 share a conserved motif that is required to bind Hdm2. Distinct complexes form between Hdm2-HIF1 and Hdm2-p53 as determined by immunoprecipitation of nuclear extracts and in vitro. The Hdm2 antagonist Nutlin3 prevents the association between Hdm2 and HIF1. The vascular endothelial growth factor (VEGF) gene is a transcriptional target of HIF1, and under normoxic or hypoxic conditions, Hdm2 increases HIF1 activity to induce VEGF production. Blocking the association of Hdm2 and HIF1 by Nutlin3, or ablating Hdm2 expression, diminished the level of VEGF under conditions of normoxia or hypoxia. Our findings establish a unique role for Nutlin3 in attenuating VEGF induction by preventing the association of Hdm2 with HIF1. [Cancer Res 2007;67(2):450–4]

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