Biology of hypoxia-inducible factor-2alpha in development and disease - PubMed (original) (raw)

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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.

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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.

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