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J. Biol. Chem., Vol. 282, Issue 51, 37064-37073, December 21, 2007

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Calcineurin Promotes Hypoxia-inducible Factor 1 Expression by Dephosphorylating RACK1 and Blocking RACK1 Dimerization^*

Ye V. Liu¹, Maimon E. Hubbi^¶, Fan Pan^||, Karin R. McDonald, Malini Mansharamani^**, Robert N. Cole^**, Jun O. Liu^||, and Gregg L. Semenza²

From the Vascular Program, Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, ^¶Graduate Training Program in Cellular and Molecular Medicine, the ^||Department of Pharmacology and Molecular Sciences, the ^**Mass Spectrometry/Proteomics Facility, Department of Biological Chemistry, and the Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Oxygen homeostasis represents an essential organizing principle of metazoan evolution and biology. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of transcriptional responses to changes in O₂ concentration. HIF-1 is a heterodimer of HIF-1 and HIF-1β subunits. O₂-dependent degradation of the HIF-1 subunit is mediated by prolyl hydroxylase, von Hippel-Lindau protein (VHL)/Elongin-C E3 ubiquitin ligase, and the proteasome. O₂-independent degradation of HIF-1 is regulated by the competition of RACK1 and HSP90 for binding to HIF-1. RACK1 binding results in the recruitment of the Elongin-C E3 ubiquitin ligase, leading to VHL-independent ubiquitination and degradation of HIF-1. In this report, we show that calcineurin inhibits the ubiquitination and proteasomal degradation of HIF-1. Calcineurin is a serine/threonine phosphatase that is activated by calcium and calmodulin. The phosphatase activity of calcineurin is required for its regulation of HIF-1. RACK1 binds to the catalytic domain of calcineurin and is required for HIF-1 degradation induced by the calcineurin inhibitor cyclosporine A. Elongin-C and HIF-1 each bind to RACK1 and dimerization of RACK1 is required to recruit Elongin-C to HIF-1. Phosphorylation of RACK1 promotes its dimerization and dephosphorylation by calcineurin inhibits dimerization. Serine 146 within the dimerization domain is phosphorylated and mutation of serine 146 impairs RACK1 dimerization and HIF-1 degradation. These results indicate that intracellular calcium levels can regulate HIF-1 expression by modulating calcineurin activity and RACK1 dimerization.

Received for publication, June 18, 2007 , and in revised form, October 4, 2007.

^* This work was supported by National Institutes of Health NHLBI Grant N01-HV28180. 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.

¹ Present address: Novavax, Inc., 9920 Belward Campus Dr., Rockville, MD 20850.

² To whom correspondence should be addressed: Broadway Research Bldg., Suite 671, 733 N. Broadway, Baltimore, MD 21205. Fax: 443-287-5618; E-mail: gsemenza{at}jhmi.edu.

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