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J. Biol. Chem., Vol. 280, Issue 13, 13019-13028, April 1, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/13/13019    most recent M411766200v1 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 Rahmani, M. Articles by McManus, B. M. Search for Related Content PubMed PubMed Citation Articles by Rahmani, M. Articles by McManus, B. M. Social Bookmarking                      What's this?

Regulation of the Versican Promoter by the -Catenin-T-cell Factor Complex in Vascular Smooth Muscle Cells^*

Maziar Rahmani, Jason T. Read, Jon M. Carthy, Paul C. McDonald, Brian W. Wong, Mitra Esfandiarei, Xiaoning Si, Zongshu Luo, Honglin Luo, Paul S. Rennie, and Bruce M. McManus¶

From the James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada and Prostate Center, Vancouver General Hospital, Vancouver, British Columbia V6T 2B5, Canada

The proteoglycan versican is pro-atherogenic and central to vascular injury and repair events. We identified the signaling pathways and promoter elements involved in regulation of versican expression in vascular smooth muscle cells. Phosphatidylinositol 3-kinase inhibitor, LY294002, significantly decreased versican-luciferase (Luc) promoter activity and endogenous mRNA levels. We further examined the roles of protein kinase B and glycogen synthase kinase (GSK)-3, downstream effectors of phosphatidylinositol 3-kinase, in the regulation of versican transcription. Co-transfection of dominant negative and constitutively active protein kinase B constructs with a versican-Luc construct decreased and increased promoter activity, respectively. Inhibition of GSK-3 activity by LiCl augmented accumulation of -catenin and caused induction of versican-Luc activity as well as versican mRNA levels. -Catenin has no DNA binding domain, therefore it cannot directly induce transcription of the versican promoter. Software analysis of the versican promoter revealed two potential binding sites for T-cell factors (TCFs), proteins that confer transcriptional activation of -catenin. Electrophoretic mobility shift and supershift assays revealed specific binding of human TCF-4 and -catenin to oligonucleotides corresponding to a potential TCF binding site in the versican promoter. In addition to binding assays, we directly assessed the dependence of versican promoter activity on TCF binding sites. Site-directed mutagenesis of the TCF site located -492 bp relative to the transcription start site markedly diminished versican-Luc activity. Co-transfection of TCF-4 with versican-Luc did not increase promoter activity, but addition of -catenin and TCF-4 significantly stimulated basal versican promoter activity. Our findings suggest that versican transcription is predominantly mediated by the GSK-3 pathway via the -catenin-TCF transcription factor complex in smooth muscle cells, wherein such regulation contributes to the normal or aberrant formation of provisional matrix in vascular injury and repair events.

Received for publication, October 15, 2004 , and in revised form, January 20, 2005.

^* This work was supported by a grant-in-aid from the Heart and Stroke Foundation of British Columbia and Yukon (to B. M. M.), doctoral research awards from the Heart and Stroke Foundation of Canada (to M. R.), a graduate fellowship of University of British Columbia (to M. R.), and a doctoral award from the Ministry of Health and Medical Education of Iran. 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.

^¶ To whom correspondence should be addressed. Tel.: 604-806-8586; Fax: 604-806-9274; E-mail: bmcmanus{at}mrl.ubc.ca.

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