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J. Biol. Chem., Vol. 281, Issue 6, 3040-3047, February 10, 2006

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A Novel Functional Interaction between the Sp1-like Protein KLF13 and SREBP-Sp1 Activation Complex Underlies Regulation of Low Density Lipoprotein Receptor Promoter Function^*

Sekar Natesampillai, Martin E. Fernandez-Zapico, Raul Urrutia, and Johannes D. Veldhuis¹

From the Endocrine Research Unit and Gastroenterology Research Unit, Department of Internal Medicine, Mayo School of Graduate Medical Education, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Cholesterol homeostasis is regulated by a family of transcription factors designated sterol regulatory element-binding proteins (SREBPs). Precise control of SREBP-targeted genes requires additional interactions with co-regulatory transcription factors. In the case of the low density lipoprotein receptor (LDLR), SREBP cooperates with the specificity protein Sp1 to activate the promoter. In this report, we describe a novel pathway in LDLR transcriptional regulation distinct from the SREBP-Sp1 activation complex involving the Sp1-like protein Krueppel-like factor 13 (KLF13). Using a combination of RNA interference, electrophoretic mobility shift, chromatin immunoprecipitation, and reporter assays, deletion, and site-directed mutagenesis, we demonstrated that KLF13 mediates repression in a DNA context-selective manner. KLF13 repression of LDLR promoter activity appears to be needed to keep the receptor silent, a state that can be antagonized by Sp1, SREBP, and inhibitors of histone deacetylase activity. Chromatin immunoprecipitation assay confirmed that KLF13 binds proximal LDLR DNA sequences in vivo and that exogenous oxysterol up-regulates such binding. Together these studies identify a novel regulatory pathway in which gene repression by KLF13 must be overcome by the Sp1-SREBP complex to activate the LDLR promoter. Therefore, these data should replace a pre-existent and more simple paradigm that takes into consideration only the induction of the activator proteins Sp1-SREBP as necessary for LDLR promoter drive without including default repression, such as that by KLF13, of the LDLR gene.

Received for publication, August 25, 2005 , and in revised form, November 9, 2005.

^* This work was supported by National Institutes of Health (NIH) Grant R01 HD16393 (to J. D. V.) and NIH RO1 Grants DK52913 and DK56620 (to R. U.), the Miles and Shirely Fitterman Funds for Mayo Proteomics and Genomics Studies (to R. U.), and Specialized Program of Research Excellence Grant P50-CA102701 (to R. U.). 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 nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY850382 [GenBank] , AY850383 [GenBank] , and DQ000310 [GenBank] .

¹ To whom correspondence should be addressed: Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, MN 55905. Tel.: 507-255-0906; Fax: 507-255-0901; E-mail: veldhuis.johannes{at}mayo.edu.

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