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J. Biol. Chem., Vol. 280, Issue 3, 1901-1910, January 21, 2005

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KLF11-mediated Repression Antagonizes Sp1/Sterol-responsive Element-binding protein-induced Transcriptional Activation of Caveolin-1 in Response to Cholesterol Signaling^*

Sheng Cao¶, Martin E. Fernandez-Zapico, Dongzu Jin||, Vishwajeet Puri**, Tiffany A. Cook**, Lilach O. Lerman¶¶, Xiang-Yang Zhu¶¶, Raul Urrutia**, and Vijay Shah||||

From the Gastroenterology Research Unit and Tumor Biology Program and the ^**Departments of Biochemistry and Molecular Biology, and the ^¶¶Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Cholesterol is a potent regulator of gene expression via a canonical pathway co-regulated by SREBP and Sp1. Here we establish the caveolin-1 gene promoter as a cell type-specific model for SREBP/Sp1 regulation whereby lipoprotein cholesterol depletion activates caveolin-1 transcription in endothelial type cells, but not in fibroblasts, both in vitro and in vivo. By extending this model, we describe a novel pathway distinct from the prototypical SREBP/Sp1 regulatory loop involving the Sp1-like protein, KLF11. Through a combination of RNA interference, chromatin immunoprecipitation assays, electrophoretic mobility shift assays, and reporter assays, we demonstrate that in the presence of cholesterol, KLF11 acts as a dominant repressor of the caveolin-1 gene. Mechanistically, cholesterol depletion results in displacement of KLF11 from an Sp1 site flanking an SRE, indicating that activation by SREBP/Sp1 requires antagonism of KLF11 repression. The displacement of KLF11 results from both a down-regulation of its expression and competition by Sp1 for DNA binding. Therefore, these studies identify a novel pathway whereby KLF11 repression is coordinated with Sp1/SREBP activation of cholesterol-dependent gene expression in a cell type-specific manner and outline the mechanisms by which these functions are achieved.

Received for publication, July 14, 2004 , and in revised form, October 14, 2004.

^* These studies were supported by National Institutes of Health Grants R01-59615 and R01-59388 (to V. S.) and DK 52913 (to R. U.), American Heart Association Scientist Development Grant AHA04-35063N (to S. C.), and an American Heart Association Postdoctoral Fellowship Award (to V. P.). 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.

These authors contributed equally to this work.

^|| Present address: University of Rochester, Rochester, NY 14623.

Present address: Torrey Pines Research Institute, 3550 General Atomics Ct., Bldg. 2, Rm. 114, San Diego, CA 92121.

Present address: New York University, 1009 Main Bldg., 100 Washington Sq. E., New York, NY 10003-6688.

^¶ To whom correspondence may be addressed: GI Research Unit, Al 2-435, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Tel.: 507-255-5047; Fax: 507-255-6318; E-mail: cao.sheng{at}mayo.edu. |||| To whom correspondence may be addressed: GI Research Unit, Al 2-435, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Tel.: 507-255-5040; Fax: 507-255-6318; E-mail: shah.vijay{at}mayo.edu.

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