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J. Biol. Chem., Vol. 282, Issue 31, 22638-22650, August 3, 2007

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The Human Mucin MUC4 Is Transcriptionally Regulated by Caudal-related Homeobox, Hepatocyte Nuclear Factors, Forkhead Box A, and GATA Endodermal Transcription Factors in Epithelial Cancer Cells^*

Nicolas Jonckheere¹², Audrey Vincent¹³, Michaël Perrais, Marie-Paule Ducourouble, Anita Korteland-van Male, Jean-Pierre Aubert, Pascal Pigny, Kermit L. Carraway^¶, Jean-Noël Freund^||, Ingrid B. Renes^**, and Isabelle Van Seuningen⁴

From the INSERM, U560, Place de Verdun, Lille, F-59045, France, the Department of Pediatrics, Divisions of Gastroenterology and Nutrition and ^**Neonatology, Erasmus MC and Sophia Children's Hospital, Rotterdam, 3015GE The Netherlands, the ^¶Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, Florida 33136, and the ^||INSERM, U682, 3 avenue Molière, Strasbourg F-67200, France

The human gene MUC4 encodes a large transmembrane mucin that is developmentally regulated and expressed along the undifferentiated pseudostratified epithelium, as early as 6.5 weeks during fetal development. Immunohistochemical analysis of Muc4 expression in developing mouse lung and gastrointestinal tract showed a different spatio-temporal pattern of expression before and after cytodifferentiation. The molecular mechanisms governing MUC4 expression during development are, however, unknown. Hepatocyte nuclear factors (HNF), forkhead box A (FOXA), GATA, and caudal-related homeobox transcription factors (TFs) are known to control cell differentiation of gut endoderm derived-tissues during embryonic development. They also control the expression of cell- and tissue-specific genes and may thus control MUC4 expression. To test this hypothesis, we studied and deciphered the molecular mechanisms responsible for MUC4 transcriptional regulation by these TFs. Experiments using small interfering RNA, cell co-transfection, and site-directed mutagenesis indicated that MUC4 is regulated at the transcriptional level by CDX-1 and -2, HNF-1 and -1, FOXA1/A2, HNF-4 and -4, and GATA-4, -5, and -6 factors in a cell-specific manner. Binding of TFs was assessed by chromatin immunoprecipitation, and gel-shift assays. Altogether, these results demonstrate that MUC4 is a target gene of endodermal TFs and thus point out an important role for these TFs in regulating MUC4 expression during epithelial differentiation during development, cancer, and repair.

Received for publication, January 31, 2007 , and in revised form, June 5, 2007.

^* This work was supported by the Association de Recherche sur le Cancer Grant 5785 (to I. V. S.), the Ligue Régionale du Pas de Calais Contre le Cancer (to I. V. S.), the Association François Aupetit (to I. V. S.), a INSERM-NWO travel grant (to I. V. S. and I. B. R.), and National Institutes of Health Grant CA52498 (to K. L. C.). 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–S7 and Tables S1–S4.

¹ Both authors participated equally to this work.

² Recipient of a Centre Hospitalier Régional et Universitaire de Lille-Région Nord-Pas de Calais Ph.D. fellowship.

³ Recipient of an INSERM-Région Nord-Pas de Calais Ph.D. fellowship.

⁴ To whom correspondence should be addressed. Tel.: 33-320-29-88-67; Fax: 33-320-53-85-62; E-mail: isabelvs{at}lille.inserm.fr.

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