Nur77 activated by hypoxia-inducible factor-1alpha overproduces proopiomelanocortin in von Hippel-Lindau-mutated renal cell carcinoma.
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-1alpha, but not HIF-2alpha, 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-1alpha. 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.
Choi
Ji-Woong
JW
Department of Biochemistry and Molecular Biology, Cancer Research Institute, Seoul, South Korea.
Park
Sang Chul
SC
Kang
Gyeong Hoon
GH
Liu
Jun O
JO
Youn
Hong-Duk
HD
D019943:Amino Acid Substitution; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D003035:Cobalt / Q000494:pharmacology; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007680:Kidney Neoplasms / Q000235:genetics*; D009154:Mutation; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics*
D017931:DNA Primers; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D003035:Cobalt; D011333:Pro-Opiomelanocortin; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; C018021:cobaltous chloride