FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity

  1. Patrick C. Mahon1,3,
  2. Kiichi Hirota1,2,3, and
  3. Gregg L. Semenza1,4
  1. 1Institute of Genetic Medicine, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914, USA; 2Department of Anesthesia, Kyoto University Hospital, Kyoto University, Kyoto, 606–8507, Japan

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a master regulator of oxygen homeostasis that controls angiogenesis, erythropoiesis, and glycolysis via transcriptional activation of target genes under hypoxic conditions. O2-dependent binding of the von Hippel-Lindau (VHL) tumor suppressor protein targets the HIF-1α subunit for ubiquitination and proteasomal degradation. The activity of the HIF-1α transactivation domains is also O2 regulated by a previously undefined mechanism. Here, we report the identification of factor inhibiting HIF-1 (FIH-1), a protein that binds to HIF-1α and inhibits its transactivation function. In addition, we demonstrate that FIH-1 binds to VHL and that VHL also functions as a transcriptional corepressor that inhibits HIF-1α transactivation function by recruiting histone deacetylases. Involvement of VHL in association with FIH-1 provides a unifying mechanism for the modulation of HIF-1α protein stabilization and transcriptional activation in response to changes in cellular O2 concentration.

Keywords

Footnotes

  • 3 These authors contributed equally to this work.

  • 4 Corresponding author.

  • E-MAIL gsemenza{at}jhmi.edu; FAX (410) 955-0484.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.924501.

    • Received July 2, 2001.
    • Accepted August 21, 2001.
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