Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2008 Apr;15(4):628-34.
doi: 10.1038/cdd.2008.17. Epub 2008 Feb 15.

Biology of hypoxia-inducible factor-2alpha in development and disease

S A Patel  1 , M C Simon
Affiliations
Review

Biology of hypoxia-inducible factor-2alpha in development and disease

S A Patel et al. Cell Death Differ. 2008 Apr.

Abstract

The transcriptional response to hypoxia is primarily mediated by two hypoxia-inducible factors--HIF-1alpha and HIF-2alpha. While these proteins are highly homologous, increasing evidence suggests they have unique transcriptional targets and differential impact on tumor growth. Furthermore, non-transcriptional effects of the HIF-alpha subunits, including effects on the Notch and c-Myc pathways, contribute to their distinct functions. HIF-2alpha transcriptional targets include genes involved in erythropoiesis, angiogenesis, metastasis, and proliferation. Therefore, HIF-2alpha contributes significantly to both normal physiology as well as tumorigenesis. Here, we summarize the function of HIF-2alpha during development as well as its contribution to pathologic conditions, such as tumors and vascular disease.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Structure of HIF-2α including the bHLH DNA binding domain, PAS domain and transactivation domains (TADs). Prolyl hydroxylases (PHDs) hydroxylate proline residues 405 and 531 in the oxygen-dependent degradation (ODD) of HIF-2α under normoxic conditions, targeting it for degradation by the proteosome. In addition, hydroxylation of asparagine 847 in the C-terminal TAD by factor-inhibiting HIF (FIH-1) inhibits interaction with the co-activators CBP/p300.
Figure 2
Figure 2
A. Transcription-dependent functions. Ets family transcription factors have been shown to cooperate specifically with HIF-2α to activate select target genes (e.g. PAI-1, EPO, CITED-2). B. Transcription-independent activities. HIF-2α regulates the activity of transcription factors such as Notch and c-Myc, thereby influencing cell proliferation, metabolism and differentiation.
Figure 3
Figure 3
The HIF-α subunits may mediate different adaptive responses to hypoxia. HIF-2α appears to be stabilized at higher O2 levels and displays fewer growth inhibitory properties than HIF-1α Moreover, prolonged accumulation of HIF-2α suggests it could be important for adaptation to chronic hypoxia.
See this image and copyright information in PMC

References

    1. Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47. - PubMed
    1. Covello KL, Simon MC. HIFs, hypoxia, and vascular development. Curr Top Dev Biol. 2004;62:37–54. - PubMed
    1. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62. - PubMed
    1. Gu YZ, Hogenesch JB, Bradfield CA. The PAS superfamily: sensors of environmental and developmental signals. Annu Rev Pharmacol Toxicol. 2000;40:519–61. - PubMed
    1. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292:468–72. - PubMed

Publication types

Substances