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

Mol Oncol. 2007 Jun;1(1):55-71. doi: 10.1016/j.molonc.2007.02.002. Epub 2007 Mar 14.

Abstract

Transforming growth factor beta (TGF-beta) suppresses epithelial cell growth. We have identified a new target gene of the TGF-beta/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-beta1-induced cytostatic response. Moreover, ectopic Meox2 suppressed epithelial cell proliferation in cooperation with TGF-beta1, 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-beta. Thus, Meox2 is primarily involved in the TGF-beta tumor suppressor pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Epithelial Cells / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Mice
  • RNA Interference
  • Response Elements / genetics
  • Response Elements / physiology*
  • Smad Proteins / genetics
  • Smad Proteins / metabolism
  • Transforming Growth Factor beta1 / metabolism*
  • Transforming Growth Factor beta1 / pharmacology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Homeodomain Proteins
  • MEOX2 protein, human
  • Meox2 protein, mouse
  • Smad Proteins
  • TP53 protein, human
  • Transforming Growth Factor beta1
  • Tumor Suppressor Protein p53