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

J. Biol. Chem., Vol. 281, Issue 31, 21698-21709, August 4, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/31/21698    most recent M601083200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dhar, S. K. Articles by Clair, D. K. St. Search for Related Content PubMed PubMed Citation Articles by Dhar, S. K. Articles by Clair, D. K. St. Social Bookmarking                      What's this?

Specificity Protein 1-dependent p53-mediated Suppression of Human Manganese Superoxide Dismutase Gene Expression^*

From the Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536

Manganese superoxide dismutase (MnSOD) is a primary antioxidant enzyme necessary for the survival of aerobic life. Previously, we demonstrated that specificity protein 1 (Sp1) is essential for the basal transcription of the MnSOD gene. We also identified nucleophosmin (NPM), an RNA-binding protein, as an important co-activator of NF-B in the induction of MnSOD by cytokine and tumor promoter. Here, using chromatin immunoprecipitation (ChIP) analysis, we demonstrate that Sp1 and NPM interact in vivo to enhance NF-B-mediated MnSOD induction. Interaction between NPM and Sp1 or NF-B at the promoter and enhancer of the MnSOD gene in vivo were verified by the presence of the PCR products from the promoter and enhancer elements in the ChIP assay. Unexpectedly, we also found p53, another transcription factor, to be a component of the complex detected by ChIP assay. The presence of p53 in this transcription complex was verified by immunoprecipitation of p53 proteins with antibody to Sp1 in nuclear extracts. Using a vector expressing full-length p53 cDNA, we demonstrated that p53 overexpression suppresses MnSOD mRNA and protein levels. Consistent with the negative role of p53 in the expression of the MnSOD gene, expression of small interfering RNA for p53 leads to an increase of MnSOD mRNA and protein levels. Using ChIP assays and immunoprecipitation, we further demonstrated that p53 interacts with Sp1 to suppress both the constitutive and 12-O-tetradecanoylphorbol-13-acetate-stimulated expression of the MnSOD gene. Inhibition of the MnSOD gene by p53 was abolished when Sp1 sites on the MnSOD promoter were mutated or when the Sp1 protein was reduced by siRNA approaches. Because expression of MnSOD protects against cell death, our findings reveal a previously unrecognized mechanism of p53-mediated cell death and demonstrate an intricate relationship between the positive and negative control of MnSOD expression.

Received for publication, February 3, 2006 , and in revised form, May 26, 2006.

^* This work was supported by National Institutes of Health Grants CA 49797, CA 94853, CA73599, and AG 05119 (to D. K. St. C.). 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 To whom correspondence should be addressed. Tel.: 859-257-3959; Fax: 859-323-1059; E-mail: DSTL00{at}pop.uky.edu.

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

This article has been cited by other articles:

				J. D. Miller, Y. Chu, R. M. Brooks, W. E. Richenbacher, R. Pena-Silva, and D. D. Heistad Dysregulation of Antioxidant Mechanisms Contributes to Increased Oxidative Stress in Calcific Aortic Valvular Stenosis in Humans J. Am. Coll. Cardiol., September 2, 2008; 52(10): 843 - 850. [Abstract] [Full Text] [PDF]

				S. K. Dhar, Y. Xu, T. Noel, and D. K. St Clair Chronic exposure to 12-O-tetradecanoylphorbol-13-acetate represses sod2 induction in vivo: the negative role of p50 Carcinogenesis, December 1, 2007; 28(12): 2605 - 2613. [Abstract] [Full Text] [PDF]