Abstract
Adaptation to low oxygen tension (hypoxia) in cells and tissues leads to the transcriptional induction of a series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival. The primary factor mediating this response is the hypoxia-inducible factor-1 (HIF-1), an oxygen-sensitive transcriptional activator. HIF-1 consists of a constitutively expressed subunit HIF-1β and an oxygen-regulated subunit HIF-1α (or its paralogs HIF-2α and HIF-3α). The stability and activity of the α subunit of HIF are regulated by its post-translational modifications such as hydroxylation, ubiquitination, acetylation, and phosphorylation. In normoxia, hydroxylation of two proline residues and acetylation of a lysine residue at the oxygen-dependent degradation domain (ODDD) of HIF-1α trigger its association with pVHL E3 ligase complex, leading to HIF-1α degradation via ubiquitin-proteasome pathway. In hypoxia, the HIF-1α subunit becomes stable and interacts with coactivators such as cAMP response element-binding protein binding protein/p300 and regulates the expression of target genes. Overexpression of HIF-1 has been found in various cancers, and targeting HIF-1 could represent a novel approach to cancer therapy.
Footnotes
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ABBREVIATIONS: HIF-1, hypoxia-inducible factor-1; HRE, hypoxia response element; ARNT, aryl hydrocarbon nuclear translocator; PAS, Per-ARNT-Sim; bHLH, basic helix-loop-helix; TAD, transactivation domains; CBP/p300, cAMP response element-binding protein binding protein; ODDD, oxygen-dependent degradation domain; 2-OG, 2-oxoglutarate; PHD, prolyl hydroxylase domain; VHL, von Hippel-Lindau; FIH-1, factor inhibiting HIF-1; ARD1, arrest-defective-1; MAPK, mitogen-activated protein kinase; VEGF, vascular endothelial cell growth factor; PTEN, phosphatase and tensin homolog deleted on chromosome 10; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; PD98095, 2-(2-amino-3-methoxyphenyl)-oxanphthalen-4-one; PI3K, phosphoinositide-3 kinase; YC-1, 3-(5′-hydroxy-methyl-2′-furyl)-1-benzylindazole.
- Received May 25, 2006.
- Accepted August 2, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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