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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism*
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Elongin
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
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Models, Biological
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Nuclear Receptor Subfamily 4, Group A, Member 1
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PC12 Cells
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Protein Binding
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Protein Processing, Post-Translational*
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Protein Structure, Tertiary
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Rats
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Receptors, Cytoplasmic and Nuclear / chemistry
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, Steroid / chemistry
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Receptors, Steroid / metabolism*
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Thermodynamics
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Transcription Factors / chemistry
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Transcription Factors / metabolism*
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Transcriptional Activation / genetics
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Ubiquitination
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Up-Regulation / genetics*
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Von Hippel-Lindau Tumor Suppressor Protein / antagonists & inhibitors*
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Von Hippel-Lindau Tumor Suppressor Protein / chemistry
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
Substances
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DNA-Binding Proteins
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ELOC protein, human
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Eloc protein, rat
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Elongin
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Hypoxia-Inducible Factor 1, alpha Subunit
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NR4A1 protein, human
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Nr4a1 protein, rat
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Receptors, Cytoplasmic and Nuclear
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Receptors, Steroid
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Transcription Factors
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Von Hippel-Lindau Tumor Suppressor Protein