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Vol. 15, No. 20, pp. 2675-2686, October 15, 2001
and VHL to mediate repression of HIF-1 transcriptional activity
1 Institute of Genetic Medicine, Departments of Pediatrics
and Medicine, The Johns Hopkins University School of Medicine,
Baltimore, Maryland 21287-3914, USA; 2 Department of Anesthesia,
Kyoto University Hospital, Kyoto University, Kyoto, 606-8507, Japan
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-1
subunit for ubiquitination and proteasomal degradation. The activity of the HIF-1 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-1 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-1 transactivation function by
recruiting histone deacetylases. Involvement of VHL in association with
FIH-1 provides a unifying mechanism for the modulation of HIF-1
protein stabilization and transcriptional activation in response to
changes in cellular O2 concentration.
[Key Words: Corepressor; histone deacetylase; hypoxia; transactivation]
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