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J. Biol. Chem., Vol. 283, Issue 23, 16084-16092, June 6, 2008

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CUL2 Is Required for the Activity of Hypoxia-inducible Factor and Vasculogenesis^*

Yutaka Maeda, Takuji Suzuki, Xiufang Pan, Gang Chen, Songqin Pan, Thomas Bartman, and Jeffrey A. Whitsett¹

From the Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039 and the W. M. Keck Proteomics Laboratory, Institute for Integrative Genome Biology, and Department of Botany and Plant Sciences, University of California, Riverside, California 92521

CULLIN 2 (CUL2) is a component of the ElonginB/C-CUL2-RBX-1-Von Hippel-Lindau (VHL) tumor suppressor complex that ubiquitinates and degrades hypoxia-inducible factor (HIF). HIF is a transcription factor that mediates the expression of hypoxia-sensitive genes, including vascular endothelial growth factor (VEGF), which in turn regulates vasculogenesis. Whereas CUL2 participates in the degradation of HIF, the potential role of CUL2 in the regulation of other cellular processes is less well established. In the present study, suppression of CUL2 expression by Cul2 siRNA inhibited HIF transcriptional activation of the VEGF gene in vitro, indicating that CUL2 plays a role distinct from its known function in HIF degradation. Because ARNT heterodimerizes with HIF, we assessed whether CUL2 influenced ARNT expression. Cul2 siRNA inhibited the expression of endogenous ARNT. Ectopically expressed ARNT reversed the inhibition of HIF activity by Cul2 siRNA in the VEGF promoter, suggesting that CUL2 regulates HIF activation through ARNT. In 786-O cells lacking VHL, Cul2 siRNA suppressed the expression of both ARNT and VEGF, indicating that CUL2 regulates HIF activity independently of VHL. In transgenic zebrafish expressing GFP driven by the Flk promoter (a known HIF target), zCul2 morpholino blocked embryonic vasculogenesis in a manner similar to that caused by inhibition of VEGF-A. In the zebrafish embryos, zCul2 inhibited the expression of CUL2, VEGF, and Flk-GFP protein, indicating that CUL2 is required for expression of other vasculogenic HIF targets. Taken together, CUL2 is required for normal vasculogenesis, at least in part mediated by its regulation of HIF-mediated transcription.

Received for publication, December 14, 2007 , and in revised form, March 4, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant HL90156 (to J. A. W.). 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.

¹ To whom correspondence should be addressed: Div. of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 7029, Cincinnati, OH 45229-3039. Tel.: 513-636-4830; Fax: 513-636-7868; E-mail: jeff.whitsett{at}cchmc.org.

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