title: Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism.
abstract: Transforming growth factor-beta1 (TGF-beta) can be tumor suppressive, but it can also enhance tumor progression by stimulating the complex process of epithelial-to-mesenchymal transdifferentiaion (EMT). The signaling pathway(s) that regulate EMT in response to TGF-beta are not well understood. We demonstrate the acquisition of a fibroblastoid morphology, increased N-cadherin expression, loss of junctional E-cadherin localization, and increased cellular motility as markers for TGF-beta-induced EMT. The expression of a dominant-negative Smad3 or the expression of Smad7 to levels that block growth inhibition and transcriptional responses to TGF-beta do not inhibit mesenchymal differentiation of mammary epithelial cells. In contrast, we show that TGF-beta rapidly activates RhoA in epithelial cells, and that blocking RhoA or its downstream target p160(ROCK), by the expression of dominant-negative mutants, inhibited TGF-beta-mediated EMT. The data suggest that TGF-beta rapidly activates RhoA-dependent signaling pathways to induce stress fiber formation and mesenchymal characteristics.
authors.affiliation: Vanderbilt-Ingram Cancer Center, Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Bhowmick
authors.forename: M
authors.initials: M
authors.lastname: Ghiassi
authors.forename: A
authors.initials: A
authors.lastname: Bakin
authors.forename: M
authors.initials: M
authors.lastname: Aakre
authors.forename: C A
authors.initials: CA
authors.lastname: Lundquist
authors.forename: M E
authors.initials: ME
authors.lastname: Engel
authors.forename: C L
authors.initials: CL
authors.lastname: Arteaga
authors.forename: H L
authors.initials: HL
authors.lastname: Moses
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D020558:GTP Phosphohydrolases / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008907:Mink; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects; D015398:Signal Transduction; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000494:pharmacology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020558:GTP Phosphohydrolases; D020742:rhoA GTP-Binding Protein