Molecular Oncology
Volume 1, Issue 1 , Pages 55-71, June 2007

Functional role of Meox2 during the epithelial cytostatic response to TGF-β

  • Ulrich Valcourt

      Affiliations

    • Present address: Institut de Biologie et Chimie des Protéines (IBCP), UMR 5086 CNRS, Université Lyon 1, IFR 128 Biosciences Lyon-Gerland, 69367 Lyon Cedex 07, France.
    • These authors contributed equally to the work.
    • ,
  • Sylvie Thuault

      Affiliations

    • These authors contributed equally to the work.
    • ,
  • Katerina Pardali

      Affiliations

    • Present address: Molecular Medicine, Deptartment of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
    • These authors contributed equally to the work.
    • ,
  • Carl-Henrik Heldin
    • ,
  • Aristidis Moustakas

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +46 18 160414; Fax: +46 18 160420.

Ludwig Institute for Cancer Research, Uppsala University, Box 595, Biomedical Center, SE-751 24 Uppsala, Sweden

Received 6 December 2006; received in revised form 10 February 2007; accepted 12 February 2007. published online 02 April 2007.

Abstract 

Transforming growth factor β (TGF-β) suppresses epithelial cell growth. We have identified a new target gene of the TGF-β/Smad pathway, Meox2, encoding the homeodomain transcription factor that is known to regulate endothelial cell proliferation and muscle development. Knockdown of endogenous Meox2 by RNA interference prevented the TGF-β1-induced cytostatic response. Moreover, ectopic Meox2 suppressed epithelial cell proliferation in cooperation with TGF-β1, and mediated induction of the cell cycle inhibitor gene p21. Transcriptional induction of p21 by Meox2 required a distal region of the p21 promoter that spans the p53-binding site. We show that Meox2 can form protein complexes with Smads leading to cooperative regulation of p21 gene expression. Finally, we found that in cell models that undergo both cell cycle arrest and epithelial–mesenchymal transition (EMT), ectopic Meox2 failed to induce EMT and inhibited the proper EMT response to TGF-β. Thus, Meox2 is primarily involved in the TGF-β tumor suppressor pathway.

Keywords: Cell cycle, Epithelial–mesenchymal transition, Homeobox, p21Cip1/Waf1, Signal transduction, Smad, Transcription, Transforming growth factor β, Tumor suppressor

 

PII: S1574-7891(07)00005-1

doi:10.1016/j.molonc.2007.02.002

Molecular Oncology
Volume 1, Issue 1 , Pages 55-71, June 2007

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