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HIF Transcription Factors

Hypoxia Inducible Factors (HIFs) are transcription factors that are stabilized mainly in response to decreased oxygen availability. HIF stabilization results in the expression of target genes that act to maintain biological homeostasis. The HIF transcription factors consist of an unstable, constitutively expressed alpha subunit (HIF-1, HIF-2 or HIF-3) and a stable, constitutively expressed beta subunit (ARNT; also known as HIF-1 beta). The stability of HIF-1 alpha is regulated by prolyl hydroxylases 1-3 (PHD1-3). In normoxia, HIF-1 alpha is rapidly hydroxylated by PHD1-3 and subsequently degraded via the 26S Proteasome. Under hypoxic conditions, HIF-1 alpha is not degraded and is able to translocate to the nucleus where it dimerizes with ARNT to form the HIF-1 transcription factor. HIF-1 binds hypoxic response elements (HREs) within the promoters of hypoxic responsive genes and interacts with co-activators, including CBP/p300, to activate transcription. Hypoxic responsive genes code for proteins that are involved in angiogenesis, metabolism, metastasis, proliferation and survival, and stem cell renewal. HIF-2 alpha appears to be regulated in a similar manner as is HIF-1 alpha, but the mechanism by which HIF-3 alpha is regulated is less clear. HIF-1 alpha activity in tumors correlates with increased angiogenesis and tumor growth, which has led to the investigation into HIF-1 alpha as a pharmacological target in cancer research.