HIF Enhancer Pathways

Click on one of the buttons below to see either HIF repressors or HIF stability and activity during normoxia and hypoxia.

Hydroxylated PKM2 Binds HIF-1 alpha
and Increases Transactivation
Hydroxylated PKM2 Binds HIF-1 alpha
and Increases Transactivation
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PKM2
PKM2
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PHD3
PHD3
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PKM2
PKM2
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HIF-1 alpha
HIF-1 alpha
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p300/CBP
p300/CBP
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ARNT
ARNT
beta-Catenin Binds HIF-1 alpha
and Increases Transactivation
beta-Catenin Binds HIF-1 alpha
and Increases Transactivation
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Src
Src
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beta-Catenin
beta-Catenin
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HIF-1 alpha
HIF-1 alpha
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p300/CBP
p300/CBP
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ARNT
ARNT
Cbx4 Binds and SUMOylates HIF-1 alpha
to Increase Transactivation
Cbx4 Binds and SUMOylates HIF-1 alpha
to Increase Transactivation
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SENP1
SENP1
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Ubc9
Ubc9
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Cbx4
Cbx4
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HIF-1 alpha
HIF-1 alpha
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Cbx4
Cbx4
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p300/CBP
p300/CBP
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ARNT
ARNT
HIF-1 alpha
HIF-1 alpha
Phosphorylation by ERK1/2 Promotes Nuclear Retention
Phosphorylation by ERK1/2 Promotes Nuclear Retention
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ERK1/2
ERK1/2
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CRM1
CRM1
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HIF-1 alpha
HIF-1 alpha
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SART1/HAF Binds HIF-2 alpha
and Increases Transactivation
SART1/HAF Binds HIF-2 alpha
and Increases Transactivation
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SART1/HAF
SART1/HAF
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p300/CBP
p300/CBP
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ARNT
ARNT
HIF-2 alpha
HIF-2 alpha

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.

HIF Enhancer Pathways background image 1HIF Enhancer Pathways background image 2