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Received for publication May 26, 2006.
Revised August 2, 2006.
Accepted for publication August 2, 2006.
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-1
and an oxygen-regulated subunit HIF-1
(or its paralogs HIF-2 and HIF-3). The stability and activity of the subunit of HIF are regulated by its posttranslational 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-1 trigger its association with pVHL E3 ligase complex, leading to HIF-1 degradation via ubiquitin-proteasome pathway. In hypoxia, the HIF-1 subunit becomes stable and interacts with co-activators such as CBP/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.
Key words:
Transcription targets, Angiogenesis
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