Exp Mol Med.  2008 Feb;40(1):71-83. 10.3858/emm.2008.40.1.71.

Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation

• Kim BY
• Kim H
• Cho EJ
• Youn HD

• KMID: 1103590
• DOI: http://doi.org/10.3858/emm.2008.40.1.71

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.

Keyword

hypoxia-inducible factor 1; alpha subunit; orphan nuclear receptor NGFI-B; ubiquitination; VHL protein, human

MeSH Terms

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