Kelch-like 20 up-regulates the expression of hypoxia-inducible factor-2a through hypoxia- and von Hippel-Lindau tumor suppressor protein-independent regulatory mechanisms.

Biochemical and biophysical research communications

PubMedID: 21888897

Higashimura Y, Terai T, Yamaji R, Mitani T, Ogawa M, Harada N, Inui H, Nakano Y. Kelch-like 20 up-regulates the expression of hypoxia-inducible factor-2a through hypoxia- and von Hippel-Lindau tumor suppressor protein-independent regulatory mechanisms. Biochem Biophys Res Commun. 2011;413(2):201-5.
Despite their structural similarity, hypoxia-inducible factor (HIF)-1a and HIF-2a 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-2a-specific regulatory mechanism, we screened HIF-2a-associated proteins in a yeast two-hybrid system and identified kelch-like 20 (KLHL20). HIF-2a, but not HIF-1a, interacted with KLHL20. siRNA-mediated knockdown of KLHL20 decreased HIF-2a protein, but not HIF-2a mRNA or HIF-1a protein. Depletion of KLHL20 decreased hypoxia-induced HIF activity, and consequently resulted in decreased expression levels of HIF-2a-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-2a. 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-2a protein expression through mechanisms independent of hypoxia and pVHL.