KMID : 0620920080400010071
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Experimental & Molecular Medicine 2008 Volume.40 No. 1 p.71 ~ p.83
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Nur77 upregulates HIF-¥á by inhibiting pVHL-mediated degradation
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Kim Bu-Yeon
Cho Eun-Jung Kim Hyung-Soo Youn Hong-Duk
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Abstract
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In this study, we investigated the role of Nur77, an orphan nuclear receptor, in HIF-¥á transcriptional activity. We found that Nur77 associates and stabilizes HIF-1¥á via indirect interaction. Nur77 was found to interact with pVHL in vivo via the ¥á-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-1¥á and ultimately increased the stability and transcriptional activity of HIF-1¥á. 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-1¥á. Under the conditions that cobalt chloride was treated or pVHL was knocked down, Nur77 could not stabilize HIF-¥á. Moreover, Nur77 could not further stabilize HIF-2¥á in A498/VHL stable cells, which is consistent with our finding that Nur77 indirectly stabilizes HIF-¥á by binding to pVHL. Thus, our results suggest that an orphan nuclear receptor Nur77 binds to pVHL, thereby stabilizes and increases HIF-¥á transcriptional activity under the nonhypoxic conditions.
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KEYWORD
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hypoxia-inducible factor 1, alpha subunit, orphan nuclear receptor NGFI-B, ubiquitination, , VHL protein, human
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