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J. Biol. Chem., Vol. 282, Issue 24, 17517-17529, June 15, 2007

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Expression of the Rat Sterol Regulatory Element-binding Protein-1c Gene in Response to Insulin Is Mediated by Increased Transactivating Capacity of Specificity Protein 1 (Sp1)^*

Xiong Deng¹, Chandrahasa Yellaturu, Lauren Cagen, Henry G. Wilcox, Edwards A. Park, Rajendra Raghow², and Marshall B. Elam

From the Medical and Research Service, Department of Veterans Affairs Medical Center, Memphis, Tennessee 38104 and the Departments of Pharmacology and Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163

The induction of genes involved in lipid biosynthesis by insulin is mediated in part by the sterol regulatory element-binding protein-1c (SREBP-1c). SREBP-1c is directly regulated by insulin by transcriptional and post-transcriptional mechanisms. Previously, we have demonstrated that the insulin-responsive cis-acting unit of the rat SREBP-1c promoter is composed of several elements that include a sterol regulatory element, two liver X receptor elements, and a number of conserved GC boxes. Here we systematically dissected the role of these GC boxes and report that five bona fide Sp1-binding elements of the SREBP-1c promoter determine its basal and insulin-induced activation. Luciferase expression driven by the rat SREBP-1c promoter was accelerated by ectopic expression of Sp1, and insulin further enhanced the transactivation potential of Sp1. Introduction of a small interfering RNA against Sp1 reduced both basal and insulin-induced activation of the SREBP-1c promoter. We also found that Sp1 interacted with both SREBP-1c and LXR proteins and that insulin promoted these interactions. Chromatin immunoprecipitation studies revealed that insulin facilitated the recruitment of the steroid receptor coactivator-1 to the SREBP-1c promoter. These studies identify a novel mechanism by which maximal activation of the rat SREBP-1c gene expression by insulin is mediated by Sp1 and its enhanced ability to interact with other transcriptional regulatory proteins.

Received for publication, March 14, 2007 , and in revised form, April 19, 2007.

^* This work was supported in part by grants from the Office of Research and Development, Department of Veterans Affairs (to M. B. E.), from the American Heart Association (Southeast Affiliate) (to M. B. E.), the University of Tennessee Vascular Biology Center of Excellence, and by Grant DK-059368 from the National Institutes of Health (to E. A. 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.

This paper is dedicated to the memory of our wonderful colleague, Dr. Lauren Cagen, who recently passed away.

² Senior Research Career Scientist for the Department of Veterans Affairs.

¹ Recipient of a postdoctoral fellowship award from the American Heart Association, Southeast Affiliate. To whom correspondence should be addressed: Medical and Research Service, Department of Veterans Affairs Medical Center, 1030 Jefferson Ave., Memphis, TN 38104. Tel.: 901-448-5825; Fax: 901-448-7206; E-mail: xdeng{at}utmem.edu.

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