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  • Title: Kelch-like 20 up-regulates the expression of hypoxia-inducible factor-2α through hypoxia- and von Hippel-Lindau tumor suppressor protein-independent regulatory mechanisms.
    Author: Higashimura Y, Terai T, Yamaji R, Mitani T, Ogawa M, Harada N, Inui H, Nakano Y.
    Journal: Biochem Biophys Res Commun; 2011 Sep 23; 413(2):201-5. PubMed ID: 21888897.
    Abstract:
    Despite their structural similarity, hypoxia-inducible factor (HIF)-1α and HIF-2α have distinct functional properties and exhibit distinct spatiotemporal expression patterns, suggesting that the expressions of the two proteins are regulated by different mechanisms. To clarify the HIF-2α-specific regulatory mechanism, we screened HIF-2α-associated proteins in a yeast two-hybrid system and identified kelch-like 20 (KLHL20). HIF-2α, but not HIF-1α, interacted with KLHL20. siRNA-mediated knockdown of KLHL20 decreased HIF-2α protein, but not HIF-2α mRNA or HIF-1α protein. Depletion of KLHL20 decreased hypoxia-induced HIF activity, and consequently resulted in decreased expression levels of HIF-2α-responsive genes such as VEGF and CITED2. In contrast, overexpression of KLHL20 increased the expression levels and transcriptional activities of the O(2)-sensitive wild-type and O(2)-insensitive mutant forms of HIF-2α. KLHL20 siRNA also inhibited HIF-2 activity in von Hippel-Lindau tumor suppressor protein (pVHL)-deficient 786-O cells. These results indicate that KLHL20 is a novel player that regulates HIF-2α protein expression through mechanisms independent of hypoxia and pVHL.
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