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J. Biol. Chem., Vol. 280, Issue 14, 14240-14251, April 8, 2005

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Activity of Hypoxia-inducible Factor 2 Is Regulated by Association with the NF-B Essential Modulator^*

Cameron P. Bracken, Murray L. Whitelaw, and Daniel J. Peet

From the School of Molecular and Biomedical Science and the Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, South Australia, 5005, Australia

The hypoxia-inducible factors 1 (HIF-1) and 2 (HIF-2) are key regulators of the transcriptional response to low oxygen and are closely related in domain architecture, DNA binding, and activation mechanisms. Despite these similarities, targeted disruption of the HIF- genes in mice results in distinctly different phenotypes demonstrating nonredundancy of function, although the underlying mechanisms remain unclear. Here we report on the novel and specific interaction of HIF-2, but not HIF-1, with the NF-B essential modulator (NEMO) using immunoprecipitation, mammalian two-hybrid, and in vitro protein interaction assays. Reporter gene assays demonstrate that this interaction specifically enhances normoxic HIF-2 transcriptional activity, independently of the HIF-2 transactivation domain, consistent with a model by which NEMO aids CBP/p300 recruitment to HIF-2. In contrast, HIF-2 overexpression does not alter NF-B signaling, suggesting that the functional consequence of the HIF-2/NEMO interaction is limited to the HIF pathway. The specificity of NEMO for HIF-2 represents one of the few known differential protein-protein interactions between the HIF- proteins, which has important implications for the activity of HIF-2 and is also the first postulated NF-B-independent role for NEMO.

Received for publication, August 31, 2004 , and in revised form, January 11, 2005.

^* This work was supported by the National Heart Foundation of Australia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 61-18-8303-5367; Fax: 61-8-8303-4348.

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