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

J. Biol. Chem., Vol. 282, Issue 46, 33358-33366, November 16, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/46/33358    most recent M705627200v1 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 Baek, J. H. Articles by Semenza, G. L. Search for Related Content PubMed PubMed Citation Articles by Baek, J. H. Articles by Semenza, G. L. Social Bookmarking                      What's this?

Spermidine/Spermine N¹-Acetyltransferase-1 Binds to Hypoxia-inducible Factor-1 (HIF-1) and RACK1 and Promotes Ubiquitination and Degradation of HIF-1^*

From the Vascular Program, Institute for Cell Engineering, the Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, and the McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Hypoxia-inducible factor-1 (HIF-1) is a master regulator of oxygen homeostasis that controls the expression of genes encoding proteins that play key roles in angiogenesis, erythropoiesis, and glucose/energy metabolism. The stability of the HIF-1 subunit is regulated by ubiquitination and proteasomal degradation. In aerobic cells, O₂-dependent prolyl hydroxylation of HIF-1 is required for binding of the von Hippel-Lindau tumor suppressor protein VHL, which then recruits the Elongin C ubiquitin-ligase complex. SSAT2 (spermidine/spermine N-acetyltransferase-2) binds to HIF-1 and promotes its ubiquitination/degradation by stabilizing the interaction of VHL and Elongin C. Treatment of cells with heat shock protein HSP90 inhibitors induces the degradation of HIF-1 even under hypoxic conditions. HSP90 competes with RACK1 for binding to HIF-1, and HSP90 inhibition leads to increased binding of RACK1, which recruits the Elongin C ubiquitin-ligase complex to HIF-1 in an O₂-independent manner. In this work, we demonstrate that SSAT1, which shares 46% amino acid identity with SSAT2, also binds to HIF-1 and promotes its ubiquitination/degradation. However, in contrast to SSAT2, SSAT1 acts by stabilizing the interaction of HIF-1 with RACK1. Thus, the paralogs SSAT1 and SSAT2 play complementary roles in promoting O₂-independent and O₂-dependent degradation of HIF-1.

Received for publication, July 9, 2007 , and in revised form, September 6, 2007.

^* This work was supported by the Johns Hopkins Institute for Cell Engineering and by United States Public Health Service Grants R01-HL-553308 and N01-HV-28180 from the National Institutes of Health. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ To whom correspondence should be addressed: Inst. for Cell Engineering, The Johns Hopkins University School of Medicine, 733 North Broadway, Suite 671, 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:

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

				A. E. Pegg Spermidine/spermine-N1-acetyltransferase: a key metabolic regulator Am J Physiol Endocrinol Metab, June 1, 2008; 294(6): E995 - E1010. [Abstract] [Full Text] [PDF]