title: von Hippel-Lindau protein adjusts oxygen sensing of the FIH asparaginyl hydroxylase.
abstract: Hypoxia inevitably develops in rapidly growing tumors and acts as an important microenvironment that forces changes in tumor behavior. Hypoxia-inducible factor 1α (HIF-1α) is activated during hypoxia and promotes the progression of malignancy by stimulating angiogenesis and by augmenting the ability of tumors to survive. In aerobic conditions, HIF-1α is destabilized by the PHD prolyl-hydroxylases that target HIF-1α for proteolysis via the von Hippel-Lindau protein (pVHL) and further inactivated by the FIH asparaginyl-hydroxylase that precludes the recruitment of transcription coactivators. Although HIF-1α degradation is well understood, little is known about how its transcriptional activity increases gradually in response to decreasing oxygen. In particular, it has been questioned how FIH having a high affinity for oxygen regulates the HIF-1α activity in moderate hypoxia. We here found that the HIF-1α-FIH interaction is disrupted in 1-5% oxygen. Both in vitro and in vivo binding analyses revealed that pVHL acts as an adaptor for FIH to bind HIF-1α. Furthermore, because the pVHL-FIH interaction depends on oxygen tension, the FIH-mediated inactivation of HIF-1α can be exquisitely regulated according to the severity of hypoxia. Based on these findings, we propose that pVHL fine-tunes the transcriptional activity of HIF-1α in graded oxygen tensions.
authors.affiliation: Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Shan Hua
authors.initials: SH
authors.lastname: Li
authors.forename: Yang-Sook
authors.initials: YS
authors.lastname: Chun
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Lim
authors.forename: L Eric
authors.initials: LE
authors.lastname: Huang
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D006899:Mixed Function Oxygenases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010100:Oxygen