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Myeloid Translocation Gene Family Members Associate with T-Cell Factors (TCFs) and Influence TCF-Dependent Transcription

Amy C. Moore,^1, Joseph M. Amann,^1, Christopher S. Williams,^1,2,5 Emilios Tahinci,³ Tiffany E. Farmer,¹ J. Andres Martinez,⁴ Genyan Yang,^1, K. Scott Luce,¹ Ethan Lee,^3,5 and Scott W. Hiebert^1,5*

Department of Biochemistry,¹ Department of Medicine, Division of Gastroenterology,² Department of Cell and Developmental Biology,³ Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition,⁴ Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232⁵

Received 11 July 2007/ Returned for modification 10 September 2007/ Accepted 12 November 2007

Canonical Wnt signaling is mediated by a molecular "switch" that regulates the transcriptional properties of the T-cell factor (TCF) family of DNA-binding proteins. Members of the myeloid translocation gene (MTG) family of transcriptional corepressors are frequently disrupted by chromosomal translocations in acute myeloid leukemia, whereas MTG16 may be inactivated in up to 40% of breast cancer and MTG8 is a candidate cancer gene in colorectal carcinoma. Genetic studies imply that this corepressor family may function in stem cells. Given that mice lacking Myeloid Translocation Gene Related-1 (Mtgr1) fail to maintain the secretory lineage in the small intestine, we surveyed transcription factors that might recruit Mtgr1 in intestinal stem cells or progenitor cells and found that MTG family members associate specifically with TCF4. Coexpression of β-catenin disrupted the association between these corepressors and TCF4. Furthermore, when expressed in Xenopus embryos, MTG family members inhibited axis formation and impaired the ability of β-catenin and XLef-1 to induce axis duplication, indicating that MTG family members act downstream of β-catenin. Moreover, we found that c-Myc, a transcriptional target of the Wnt pathway, was overexpressed in the small intestines of mice lacking Mtgr1, thus linking inactivation of Mtgr1 to the activation of a potent oncogene.

Published ahead of print on 26 November 2007.

A.C.M. and J.M.A. contributed equally to this study.

Present address: National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, N.E., Atlanta, GA 30333.