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Int J Biochem Cell Biol. 2011 May;43(5):795-804. doi: 10.1016/j.biocel.2011.02.004. Epub 2011 Feb 21.

von Hippel-Lindau protein adjusts oxygen sensing of the FIH asparaginyl hydroxylase.

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Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Republic of Korea.


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.

[Indexed for MEDLINE]

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