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U19/Eaf2 Binds to and Stabilizes von Hippel-Lindau Protein

¹ Department of Urology and ² University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania; Departments of ³ Urology and ⁴ Pathology and ⁵ Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and ⁶ Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, People's Republic of China

Requests for reprints: Zhou Wang, University of Pittsburgh Medical College, Suite G40, 5200 Centre Avenue, Pittsburgh, PA 15232. Phone: 412-623-3903; Fax: 412-623-3904; E-mail: wangz2{at}upmc.edu.

Key Words: tumor suppressor • U19/Eaf2 • VHL

Studies have firmly established a key regulatory role for the tumor suppressor pVHL in the regulation of the vascular system and normal spermatogenesis. Here, we report that knockout of the newly identified tumor suppressor U19/Eaf2 also caused vascular system abnormalities and aspermatogenesis, suggesting a potential link between U19/Eaf2 and pVHL. Coimmunoprecipitation and in vitro binding assays showed an association between U19/Eaf2 and pVHL, whereas deletion mutagenesis revealed the requirement of the NH₂ terminus of U19/Eaf2 and both the and β domains of pVHL for this binding. U19/Eaf2 stabilizes pVHL, as shown by protein stability and pulse-chase studies. Testes and mouse embryonic fibroblasts (MEF) derived from U19/Eaf2 knockout mice expressed reduced levels of pVHL, indicating that full in vivo expression of pVHL indeed requires U19/Eaf2. As expected, U19/Eaf2 knockout MEF cells exhibited an increased level and activity of hypoxia-inducible factor 1 (HIF1), a protein typically regulated via a pVHL-mediated degradation pathway. Furthermore, angiogenesis in a Matrigel plug assay was significantly increased in U19/Eaf2 knockout mice. The above observations argue that U19/Eaf2 can modulate HIF1 and angiogenesis, possibly via direct binding and stabilization of pVHL. [Cancer Res 2009;69(6):2599–606]

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