This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Choi, J.-W. Articles by Youn, H.-D. Search for Related Content PubMed PubMed Citation Articles by Choi, J.-W. Articles by Youn, H.-D.

Nur77 Activated by Hypoxia-Inducible Factor-1 Overproduces Proopiomelanocortin in von Hippel-Lindau-Mutated Renal Cell Carcinoma

¹Department of Biochemistry and Molecular Biology, Cancer Research Institute, Seoul, South Korea; ²The Aging and Apoptosis Research Center, Seoul, South Korea; ³Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea; and ⁴Department of Pharmacology and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland

Mutation in the von Hippel-Lindau (VHL) protein associated with renal cell carcinoma causes hypoxia-inducible factor (HIF) to stabilize and consequently to induce various HIF-targeting proteins. In this study, we found that proopiomelanocortin (POMC), an adrenocorticotropic hormone precursor, is up-regulated constitutively in VHL-mutated renal cell carcinoma. A critical transcription factor responsible for POMC overproduction was identified as Nur77, a member of the orphan steroid receptor superfamily. Little is known about how VHL mutation leads to activation of Nur77. We report that Nur77 is directly regulated by HIF. We show that HIF-1, but not HIF-2, binds to a putative HIF responsive element in the Nur77 promoter, activating the expression of Nur77. Mutation or deletion of the HIF binding site in the Nur77 promoter abrogates activation of a luciferase reporter gene under the control of Nur77 promoter by HIF-1. The treatment of Nur77 antisense oligonucleotide reduces POMC transcription under hypoxic conditions. We confirmed that Nur77 and POMC are up-regulated in VHL-mutated renal cell carcinoma. In this study, we provide the first molecular evidence that Nur77 activated by HIF under hypoxic conditions regulates production of the peptide hormone precursor POMC.

This article has been cited by other articles:

				T. Shinojima, M. Oya, A. Takayanagi, R. Mizuno, N. Shimizu, and M. Murai Renal cancer cells lacking hypoxia inducible factor (HIF)-1{alpha} expression maintain vascular endothelial growth factor expression through HIF-2{alpha} Carcinogenesis, March 1, 2007; 28(3): 529 - 536. [Abstract] [Full Text] [PDF]

				R. H. Wenger, D. P. Stiehl, and G. Camenisch Integration of Oxygen Signaling at the Consensus HRE Sci. Signal., October 18, 2005; 2005(306): re12 - re12. [Abstract] [Full Text] [PDF]

				Y.-G. Yoo, M. G. Yeo, D. K. Kim, H. Park, and M.-O. Lee Novel Function of Orphan Nuclear Receptor Nur77 in Stabilizing Hypoxia-inducible Factor-1{alpha} J. Biol. Chem., December 17, 2004; 279(51): 53365 - 53373. [Abstract] [Full Text] [PDF]

				J. P. Luyendyk, W. B. Mattes, L. D. Burgoon, T. R. Zacharewski, J. F. Maddox, G. N. Cosma, P. E. Ganey, and R. A. Roth Gene Expression Analysis Points to Hemostasis in Livers of Rats Cotreated with Lipopolysaccharide and Ranitidine Toxicol. Sci., July 1, 2004; 80(1): 203 - 213. [Abstract] [Full Text] [PDF]