Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation.
In this study, we investigated the role of Nur77, an orphan nuclear receptor, in HIF-alpha transcriptional activity. We found that Nur77 associates and stabilizes HIF-1alpha via indirect interaction. Nur77 was found to interact with pVHL in vivo via the alpha-domain of pVHL. By binding to pVHL, Nur77 competed with elongin C for pVHL binding. Moreover, Nur77-binding to pVHL inhibited the pVHL-mediated ubiquitination of HIF-1alpha and ultimately increased the stability and transcriptional activity of HIF-1alpha. The ligand-binding domain of Nur77 was found to interact with pVHL and the expression of this ligand-binding domain was sufficient to stabilize and transactivate HIF-1alpha. Under the conditions that cobalt chloride was treated or pVHL was knocked down, Nur77 could not stabilize HIF-alpha. Moreover, Nur77 could not further stabilize HIF-2alpha in A498/VHL stable cells, which is consistent with our finding that Nur77 indirectly stabilizes HIF-alpha by binding to pVHL. Thus, our results suggest that an orphan nuclear receptor Nur77 binds to pVHL, thereby stabilizes and increases HIF-alpha transcriptional activity under the non-hypoxic conditions.
Kim
Bu Yeon
BY
Department of Biochemistry and Molecular Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
Kim
Hyungsoo
H
Cho
Eun Jung
EJ
Youn
Hong Duk
HD
D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D000075065:Elongin; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008954:Models, Biological; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016716:PC12 Cells; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D011987:Receptors, Steroid / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D054875:Ubiquitination; D015854:Up-Regulation / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D004268:DNA-Binding Proteins; C000616395:ELOC protein, human; C000616400:Eloc protein, rat; D000075065:Elongin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C539821:NR4A1 protein, human; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein