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[Cancer Research 64, 35-39, January 1, 2004]
© 2004 American Association for Cancer Research

Regular Articles

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

Ji-Woong Choi1, Sang Chul Park12, Gyeong Hoon Kang3, Jun O. Liu4 and Hong-Duk Youn1

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{alpha}, but not HIF-2{alpha}, 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{alpha}. 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.




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