HIF-1 and HIF-2: working alone or together in hypoxia?
Peter J. Ratcliffe
Peter J. Ratcliffe
Published April 2, 2007
Citation Information: J Clin Invest. 2007;117(4):862-865. https://doi.org/10.1172/JCI31750.
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Commentary

HIF-1 and HIF-2: working alone or together in hypoxia?

Abstract

Erythropoietin (EPO) is the hormonal regulator of red cell production and provided the paradigm for oxygen-regulated gene expression that led to the discovery of hypoxia-inducible factor (HIF). In this issue of the JCI, Rankin and colleagues show, using targeted gene inactivation, that induction of Epo expression in murine liver is dependent on the integrity of HIF-2α, and not HIF-1α (see the related article beginning on page 1068). These results demonstrate distinct functions for different HIF-α isoforms that could potentially be exploited in therapeutic approaches to anemia.

Authors

Peter J. Ratcliffe

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Figure 2

Cooperative interactions at the Epo locus that are proposed to direct preferential binding of HIF-2α.

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Cooperative interactions at the Epo locus that are proposed to direct pr...
While the isolated HRE preferentially binds HIF-1α (A), in this issue of the JCI Rankin et al. (8) show that HIF-2α binds preferentially at the HRE within the native Epo 3' enhancer (B) and propose that cooperative interactions with other transcription factors bound to the 3' enhancer, to the promoter, or to other cis-acting sequences enable HIF-2α to bind preferentially to this HRE. The position of a hepatic nuclear factor–4 (HNF-4) binding site within the enhancer, which is a candidate participant in this action, is marked.