Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation.
- Author:
Bu Yeon KIM
1
;
Hyungsoo KIM
;
Eun Jung CHO
;
Hong Duk YOUN
Author Information
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords: hypoxia-inducible factor 1; alpha subunit; orphan nuclear receptor NGFI-B; ubiquitination; VHL protein, human
- MeSH: Animals; DNA-Binding Proteins/chemistry/*metabolism; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/*genetics; Models, Biological; PC12 Cells; Protein Binding; *Protein Processing, Post-Translational; Protein Structure, Tertiary; Rats; Receptors, Cytoplasmic and Nuclear/chemistry/*metabolism; Receptors, Steroid/chemistry/*metabolism; Thermodynamics; Transcription Factors/chemistry/*metabolism; Transcriptional Activation/genetics; Ubiquitination; Up-Regulation/*genetics; Von Hippel-Lindau Tumor Suppressor Protein/*antagonists & inhibitors/chemistry/*metabolism
- From:Experimental & Molecular Medicine 2008;40(1):71-83
- CountryRepublic of Korea
- Language:English
- Abstract: 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.
