HIF Stability and Activity Pathways

Click on one of the buttons below to see how HIF transcription factors are regulated during normoxia versus hypoxia and mechanisms by which HIF repressors and HIF enhancers modulate the activity of HIF transcription factors.

PHD
PHD
HIF-1/2 alpha
HIF-1/2 alpha
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pVHL
pVHL
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HIF-1/2 alpha
HIF-1/2 alpha
HIF-1/2 alpha
HIF-1/2 alpha
26S Proteasome
26S Proteasome
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USP28
USP28
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HIF-1 alpha
HIF-1 alpha
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FBXW7
FBXW7
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HIF-1 alpha
HIF-1 alpha
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GSK-3 beta
GSK-3 beta
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SART1/HAF
SART1/HAF
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HIF-1 alpha
HIF-1 alpha
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CHIP
CHIP
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HSP70
HSP70
HIF-2 alpha
HIF-2 alpha
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Ubc9
Ubc9
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SENP1
SENP1
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RNF4/pVHL
RNF4/pVHL
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HIF-1/2 alpha
HIF-1/2 alpha
HIF-1/2 alpha
HIF-1/2 alpha
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p300/CBP
p300/CBP
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ARNT
ARNT
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SENP1
SENP1
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HIF-1 alpha
HIF-1 alpha
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PIASy
PIASy
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Ubc9
Ubc9
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HIF-1 alpha
HIF-1 alpha
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pVHL
pVHL
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26S Proteasome
26S Proteasome
Normoxia
Normoxia
Hypoxia
Hypoxia
Angiogenesis
Angiogenesis
EMT
EMT
Survival/Proliferation
Survival/Proliferation
Metastasis
Metastasis
Glycolysis
Glycolysis
Pluripotency
Pluripotency

Overview of HIF Transcription Factor Stability and Activity

Hypoxia Inducible Factors (HIFs) are transcription factors that are stabilized mainly in response to decreased oxygen availability. Stabilized HIF induces the expression of target genes that act to maintain biological homeostasis. The functional 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). Of the alpha subunits, HIF-1 alpha is the most extensively studied, followed by HIF-2 alpha and HIF-3 alpha, about which the least is known. The regulation of HIF-1 alpha and HIF-2 alpha stability during normoxia and hypoxia by the von Hippel-Lindau protein (pVHL) and other ubiquitin E3 ligases is displayed below. When HIF-1 alpha and HIF-2 alpha are stable, they are able to translocate to the nucleus where they individually dimerize with ARNT to form either the HIF-1 or HIF-2 transcription factor, respectively. HIF-1 and HIF-2 bind hypoxic response elements (HREs) within the promoters of hypoxic responsive genes and interact with co-activators, including p300/CBP, to activate transcription. Hypoxic responsive genes code for proteins that are involved in angiogenesis, epithelial-to-mesenchymal transition (EMT), survival, proliferation, metastasis, glycolysis, and pluripotency. HIF-1 and HIF-2 transcriptional activity can be modulated by both repressors and enhancers. HIF transcriptional activity can be repressed via post-translational modifications and protein-protein interactions that block the binding of HIF alpha subunits to ARNT and p300/CBP. There are also post-translational modifications and protein-protein interactions that enhance the transactivation of HIF, including SUMOylation of HIF-1 alpha by Cbx4 and the binding of SART1/HAF to HIF-2 alpha. HIF-1 alpha activity in tumors correlates with increased angiogenesis and tumor growth, which has led to the investigation of HIF-1 alpha as a pharmacological target.

To learn more, please visit our HIF Transcription Factors Research Area.

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