Epithelial to mesenchymal transition in Madin-Darby canine kidney cells is accompanied by down-regulation of Smad3 expression, leading to resistance to transforming growth factor-beta-induced growth arrest.
In normal epithelial cells, transforming growth factor-beta (TGF-beta) typically causes growth arrest in the G(1) phase of the cell cycle and may eventually lead to apoptosis. However, transformed cells lose these inhibitory responses and often instead show an increase in malignant character following TGF-beta treatment. In the canine kidney-derived epithelial cell line, MDCK, synergism between activation of the Raf/MAPK pathway and the resulting autocrine production of TGF-beta triggers transition from an epithelial to a mesenchymal phenotype. During this process, these cells become refractive to TGF-beta-induced cell cycle arrest and apoptosis. TGF-beta signals are primarily transduced to the nucleus through complexes of receptor-regulated Smads, Smad2 and Smad3 with the common mediator Smad, Smad4. Here we show that the transition from an epithelial to mesenchymal phenotype is accompanied by gradual down-regulation of expression of Smad3. Restoration of Smad3 to previous levels of expression restores the cell cycle arrest induced by TGF-beta without reverting the cells to an epithelial phenotype or impacting on the MAPK pathway. Regulation of apoptosis is not affected by Smad3 levels. These data attribute to Smad3 a critical role in the control of cell proliferation by TGF-beta, which is lost following an epithelial to mesenchymal transition.
Nicolás
Francisco J
FJ
Developmental Signalling Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Lehmann
Kerstin
K
Warne
Patricia H
PH
Hill
Caroline S
CS
Downward
Julian
J
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics*; D004285:Dogs; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007668:Kidney; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008648:Mesoderm / Q000166:cytology*; D010641:Phenotype; D051900:Smad3 Protein; D015534:Trans-Activators / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D019459:Urothelium / Q000166:cytology*
D004268:DNA-Binding Proteins; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta