Novel function of orphan nuclear receptor Nur77 in stabilizing hypoxia-inducible factor-1alpha.
Hypoxia-inducible factor-1alpha (HIF-1alpha) 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-1alpha. 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-1alpha 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-1alpha. The association of HIF-1alpha 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-1alpha stability and recovered MDM2 expression, indicating that the extracellular signal-regulated kinase pathway is critical in the Nur77-induced activation of HIF-1alpha. Together, our results demonstrate a novel function for Nur77 in the stabilization of HIF-1alpha and suggest a potential role for Nur77 in tumor progression and metastasis.
Yoo
Young-Gun
YG
Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Korea.
Yeo
Myeong Goo
MG
Kim
Dae Kyong
DK
Park
Hyunsung
H
Lee
Mi-Ock
MO
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047468:Immunoprecipitation; D051379:Mice; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D009687:Nuclear Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one