HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) All Versions of this Article: 282/51/37064    most recent M705015200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, Y. V. Articles by Semenza, G. L. Search for Related Content PubMed PubMed Citation Articles by Liu, Y. V. Articles by Semenza, G. L. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				N. Wagner, C. Jehl-Pietri, P. Lopez, J. Murdaca, C. Giordano, C. Schwartz, P. Gounon, S. N. Hatem, P. Grimaldi, and K.-D. Wagner Peroxisome proliferator-activated receptor {beta} stimulation induces rapid cardiac growth and angiogenesis via direct activation of calcineurin Cardiovasc Res, July 1, 2009; 83(1): 61 - 71. [Abstract] [Full Text] [PDF]

				S. Singh, S. M. Manda, D. Sikder, M. J. Birrer, B. A. Rothermel, D. J. Garry, and P. P. A. Mammen Calcineurin Activates Cytoglobin Transcription in Hypoxic Myocytes J. Biol. Chem., April 17, 2009; 284(16): 10409 - 10421. [Abstract] [Full Text] [PDF]

				G. L. Semenza Regulation of Oxygen Homeostasis by Hypoxia-Inducible Factor 1 Physiology, April 1, 2009; 24(2): 97 - 106. [Abstract] [Full Text] [PDF]

				P. A. Kiely, G. S. Baillie, M. J. Lynch, M. D. Houslay, and R. O'Connor Tyrosine 302 in RACK1 Is Essential for Insulin-like Growth Factor-I-mediated Competitive Binding of PP2A and {beta}1 Integrin and for Tumor Cell Proliferation and Migration J. Biol. Chem., August 22, 2008; 283(34): 22952 - 22961. [Abstract] [Full Text] [PDF]

				A. Basu, A. G. Contreras, D. Datta, E. Flynn, L. Zeng, H. T. Cohen, D. M. Briscoe, and S. Pal Overexpression of Vascular Endothelial Growth Factor and the Development of Post-Transplantation Cancer Cancer Res., July 15, 2008; 68(14): 5689 - 5698. [Abstract] [Full Text] [PDF]