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 Jonckheere, Audrey Vincent, Michaël Perrais, Marie Paule Ducourouble, Anita Korteland Van Male, Jean Pierre Aubert, Pascal Pigny, Kermit L. Carraway, Jean Noël Freund, Ingrid B. Renes, Isabelle Van Seuningen

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

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 cotransfection, and site-directed mutagenesis indicated that MUC4 is regulated at the transcriptional level by CDX-1 and -2, HNF-1α and -1β, FOXA1/A2, HNF-4α and -4γ, 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.

Original languageEnglish (US)
Pages (from-to)22638-22650
Number of pages13
JournalJournal of Biological Chemistry
Volume282
Issue number31
DOIs
StatePublished - Aug 3 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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