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J. Biol. Chem., Vol. 281, Issue 51, 39105-39113, December 22, 2006

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Disruption of an SP2/KLF6 Repression Complex by SHP Is Required for Farnesoid X Receptor-induced Endothelial Cell Migration^*

Amitava Das¹, Martin E. Fernandez-Zapico, Sheng Cao, Janet Yao, Stefano Fiorucci, Robert P. Hebbel^¶, Raul Urrutia, and Vijay H. Shah²

From the Gastroenterology Research Unit, Department of Physiology and Cancer Cell Biology Program, Mayo Clinic, Rochester, Minnesota 55905, the Dipartimento di Medicina Clinica e Sperimentale, Clinica di Gastroenterologia ed Endoscopia Digestiva, University of Perugia, Perugia 06122, Italy, and the ^¶Vascular Biology Center, Division of Hematology, Oncology, and Transplantation, University of Minnesota Medical School, Minneapolis, Minnesota 55454

The farnesoid X receptor (FXR) signaling pathway regulates bile acid and cholesterol homeostasis. Here, we demonstrate, using a variety of gain- and loss-of-function approaches, a role of FXR in the process of cell motility, which involves the small heterodimeric partner (SHP)-dependent up-regulation of matrix metalloproteinase-9. We use this observation to reveal a transcriptional regulatory mechanism involving the SP/KLF transcription factors, SP2 and KLF6. Small interference RNA-based silencing studies in combination with promoter, gel shift, and chromatin immunoprecipitation assays indicate that SP2 and KLF6 bind to the matrix metalloproteinase-9 promoter and together function to maintain this gene in a silenced state. However, upon activation of FXR, SHP interacts with SP2 and KLF6, disrupting the SP2/KLF6 repressor complex. Thus, together, these studies identify a mechanism for antagonizing Sp/KLF protein repression function via SHP, with this process regulating endothelial cell motility.

Received for publication, August 11, 2006 , and in revised form, October 10, 2006.

^* This work was supported by National Institutes of Health Grants R01-59615 and R01-59388 (to V. H. S.) and DK 52913 (to R. U.), by Pancreatic SPORE Career Development Award P50 CA102701 and Mayo Clinic Cancer Center (to M. E. F.-Z.), by American Heart Association Scientist Development Grant AHA0435063N (to S. C.), and by National Institutes of Health Grant PO1-HL076540 (to R. P. H.). 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 Figs. S1–S4.

¹ To whom correspondence may be addressed: GI Research Unit, Alfred 2-435, Mayo Clinic Rochester, 200 First St. SW, Rochester, MN 55905. Tel.: 507-255-1607; Fax: 507-255-6318; E-mail: das.amitava{at}mayo.edu. ² To whom correspondence may be addressed: GI Research Unit, Alfred 2-435, Mayo Clinic Rochester, 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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