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Originally published In Press as doi:10.1074/jbc.M208076200 on December 4, 2002

J. Biol. Chem., Vol. 278, Issue 9, 7431-7438, February 28, 2003
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Peroxisome Proliferator-activated Receptor gamma  and Transforming Growth Factor-beta Pathways Inhibit Intestinal Epithelial Cell Growth by Regulating Levels of TSC-22*

Rajnish A. GuptaDagger , Pasha Sarraf§, Jeffrey A. Brockman, Scott B. Shappell||, Laurel A. Raftery**Dagger Dagger , Timothy M. Willson§§, and Raymond N. DuBoisDagger ¶¶||||

From the Departments of ¶¶ Medicine, Dagger  Cellular and Developmental Biology, and || Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, the § Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115,  Psychiatric Genomics, Inc., Gaithersburg, Maryland 20878, ** Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, and §§ Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709

Peroxisome proliferator-activated receptor gamma  (PPARgamma ) and transforming growth factor-beta (TGF-beta ) are key regulators of epithelial cell biology. However, the molecular mechanisms by which either pathway induces growth inhibition and differentiation are incompletely understood. We have identified transforming growth factor-simulated clone-22 (TSC-22) as a target gene of both pathways in intestinal epithelial cells. TSC-22 is member of a family of leucine zipper containing transcription factors with repressor activity. Although little is known regarding its function in mammals, the Drosophila homolog of TSC-22, bunched, plays an essential role in fly development. The ability of PPARgamma to induce TSC-22 was not dependent on an intact TGF-beta 1 signaling pathway and was specific for the gamma  isoform. Localization studies revealed that TSC-22 mRNA is enriched in the postmitotic epithelial compartment of the normal human colon. Cells transfected with wild-type TSC-22 exhibited reduced growth rates and increased levels of p21 compared with vector-transfected cells. Furthermore, transfection with a dominant negative TSC-22 in which both repressor domains were deleted was able to reverse the p21 induction and growth inhibition caused by activation of either the PPARgamma or TGF-beta pathways. These results place TSC-22 as an important downstream component of PPARgamma and TGF-beta signaling during intestinal epithelial cell differentiation.

* This work was supported in part by United States Public Health Service Grants RO1DK 47279 (to R. N. D.), P030 ES-00267-29 (to R. N. D.), and P01CA-77839 (to R. N. D.) and is supported by grants from the Shiseido Company of Japan, Ltd. (to L. A. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Dagger Supported by grants from the American Cancer Society and the National Institutes of Health.

|||| Recipient of a Veterans Affairs Research Merit Grant, a Mina C. Wallace Professor of Cancer Prevention, and supported by the T. J. Martell Foundation and National Colorectal Cancer Research Alliance. To whom correspondence should be addressed: Dept. of Medicine/GI, MCN C-2104, Vanderbilt University Medical Center, 1161 21st Ave. South, Nashville, TN 37232-2279. Tel.: 615-322-5200; Fax: 615-343-6229; E-mail: raymond.dubois@vanderbilt.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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