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J. Biol. Chem., Vol. 279, Issue 51, 53365-53373, December 17, 2004

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Novel Function of Orphan Nuclear Receptor Nur77 in Stabilizing Hypoxia-inducible Factor-1^*

Young-Gun Yoo, Myeong Goo Yeo, Dae Kyong Kim, Hyunsung Park¶, and Mi-Ock Lee||

From the Department of Bioscience and Biotechnology, Sejong University, Seoul, 143-747, College of Pharmacy, Chung-Ang University, Seoul 156-756, and ^¶Department of Life Science, University of Seoul, Seoul 130-743 Korea

Hypoxia-inducible factor-1 (HIF-1) plays a central role in oxygen homeostasis by inducing the expression of a broad range of genes in a hypoxia-dependent manner. Here, we show that the orphan nuclear receptor Nur77 is an important regulator of HIF-1. Under hypoxic conditions, Nur77 protein and transcripts were induced in a time-dependent manner. When Nur77 was exogenously introduced, it enhanced the transcriptional activity of HIF-1, whereas the dominant negative Nur77 mutant abolished the function of HIF-1. The HIF-1 protein was greatly increased and completely localized in the nucleus when coexpressed with Nur77. The N-terminal transactivation domain of Nur77 was required and sufficient for the activation of HIF-1. The association of HIF-1 with von Hippel-Lindau protein was not affected, whereas that with mouse double minute 2 (MDM2) was greatly reduced in the presence of Nur77. Further we found that the expression of MDM2 was repressed at transcription level in the presence of Nur77 as well as under hypoxic conditions. Finally, PD98059 decreased Nur77-induced HIF-1 stability and recovered MDM2 expression, indicating that the extracellular signal-regulated kinase pathway is critical in the Nur77-induced activation of HIF-1. Together, our results demonstrate a novel function for Nur77 in the stabilization of HIF-1 and suggest a potential role for Nur77 in tumor progression and metastasis.

Received for publication, July 28, 2004 , and in revised form, September 16, 2004.

^* This study was supported by grants from the Ministry of Science and Technology (M1-0311-00-0089 and M1-0312-04-0002). 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. Tel.: 82-2-3408-3768; Fax: 82-2-3408-3768; E-mail: molee{at}sejong.ac.kr.

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