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.
Original language | English (US) |
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Pages (from-to) | 2675-2686 |
Number of pages | 12 |
Journal | Genes and Development |
Volume | 15 |
Issue number | 20 |
DOIs | |
State | Published - Oct 15 2001 |
Keywords
- Corepressor
- Histone deacetylase
- Hypoxia
- Transactivation
ASJC Scopus subject areas
- Genetics
- Developmental Biology