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J. Biol. Chem., Vol. 280, Issue 34, 30225-30235, August 26, 2005

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Renal Carcinoma-associated Transcription Factors TFE3 and TFEB Are Leukemia Inhibitory Factor-responsive Transcription Activators of E-cadherin^*

Chongmin Huan, Deepa Sashital¶||, Tiruneh Hailemariam, Matthew L. Kelly, and Christopher A. J. Roman**

From the Department of Microbiology and Immunology and the Morse Institute for Molecular Genetics, the Program in Molecular and Cellular Biology, the School of Graduate Studies, and the ^¶Department of Medicine, Division of Hematology and Oncology, State University of New York Downstate Medical Center, Brooklyn, New York 11203

Translocations of the genes encoding the related transcription factors TFE3 and TFEB are almost exclusively associated with a rare juvenile subset of renal cell carcinoma and lead to overexpression of TFE3 or TFEB protein sequences. A better understanding of how deregulated TFE3 and TFEB contribute to the transformation process requires elucidating more of the normal cellular processes in which they participate. Here we identify TFE3 and TFEB as cell type-specific leukemia inhibitory factor-responsive activators of E-cadherin. Overexpression of TFE3 or TFEB in 3T3 cells activated endogenous and reporter E-cadherin expression. Conversely, endogenous TFE3 and/or TFEB was required for endogenous E-cadherin expression in primary mouse embryonic fibroblasts and human embryonic kidney cells. Chromatin precipitation analyses and E-cadherin promoter reporter gene assays revealed that E-cadherin induction by TFE3 or TFEB was primarily or exclusively direct and mitogen-activated protein kinase-dependent in those cell types. In mouse embryonic fibroblasts, TFE3 and TFEB activation of E-cadherin was responsive to leukemia inhibitory factor. In 3T3 cells, TFE3 and TFEB expression also induced expression of Wilms' tumor-1, another E-cadherin activator. In contrast, E-cadherin expression in model mouse and canine renal epithelial cell lines was indifferent to inhibition of endogenous TFE3 and/or TFEB and was reduced by TFE3 or TFEB overexpression. These results reveal new cell type-specific activities of TFE3 and TFEB which may be affected by their mutation.

Received for publication, March 3, 2005 , and in revised form, June 24, 2005.

^* These studies were supported by Public Health Service Grant R21 DK065011-02 from the NIDDK, National Institutes of Health (to C.A.J. R.). 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 Data S1–S3.

^|| Present address: Marion Cancer Care Center, Marion General Hospital, 330 N. Wabash Ave., Marion, IN 46952.

^** To whom correspondence should be addressed: Dept. of Microbiology and Immunology, SUNY-Downstate Medical Center, 450 Clarkson Ave., Box 44, Brooklyn, NY 11203. E-mail: Christopher.Roman{at}Downstate.edu.

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