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

J. Biol. Chem., Vol. 283, Issue 44, 29784-29794, October 31, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/44/29784    most recent M804481200v1 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 Google Scholar Google Scholar Articles by Necela, B. M. Articles by Thompson, E. A. Search for Related Content PubMed PubMed Citation Articles by Necela, B. M. Articles by Thompson, E. A. Social Bookmarking                      What's this?

Peroxisome Proliferator-activated Receptor Down-regulates Follistatin in Intestinal Epithelial Cells through SP1^*

From the Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224

Activation of peroxisome proliferator-activated receptor (PPAR) down-regulates the expression of follistatin mRNA in intestinal epithelial cells in vivo. The mechanism of PPAR-mediated down-regulation of follistatin was investigated using non-transformed, rat intestinal epithelial cells (RIE-1). RIE cells expressed activin A, the activin receptors ActRI and ActRII, and the follistatin-315 mRNA. RIE-1 cells responded to endogenous activin A, and this response was antagonized by follistatin, as evidenced by changes in cell growth and regulation of an activin-responsive reporter. Using RIE-1 cells, we show that activation of PPAR by rosiglitazone reduced follistatin mRNA levels in a dose- and concentration-dependent manner. Down-regulation of follistatin by rosiglitazone required the DNA binding domain of PPAR and was dependent upon dimerization with the retinoid X receptor. Inhibition of follistatin expression by rosiglitazone was not associated with decreased follistatin mRNA stability, suggesting that regulation may be at the promoter level. Analysis of the follistatin promoter revealed consensus binding sites for AP-1, AP-2, and Sp1. Targeting the AP-1 pathway with SP600125, an inhibitor of JNK, and TAM67, a dominant negative c-Jun, had no effect on PPAR-mediated down-regulation of follistatin. However, the follistatin promoter was dramatically regulated by Sp1, and this regulation was inhibited by PPAR expression. Knockdown of Sp1 expression relieved repression of follistatin levels by rosiglitazone. Moreover, PPAR was found to interact with Sp1 and repress its transcriptional activation function. Collectively, our data indicate that repression of Sp1 transcriptional activity by PPAR is the underlying mechanism responsible for PPAR-mediated regulation of follistatin expression.

Received for publication, June 11, 2008 , and in revised form, August 8, 2008.

^* This work was supported by the Crohn's and Colitis Foundation and the Mayo Foundation. 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 Fig. S1.

¹ To whom correspondence should be addressed: Dept. of Cancer Biology, Griffin Cancer Research Bld., Rm. 241, Mayo Clinic Comprehensive Cancer Center, 4500 San Pablo Road, Jacksonville, FL 32224. Tel.: 904-953-6039; Fax: 904-953-0277; E-mail: necela.brian{at}mayo.edu.

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