Abstract
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.
Highlights
Transforming growth factor- (TGF-)1 plays two rather paradoxical roles in cancer [1,2,3]
These data attribute to Smad3 a critical role in the control of cell proliferation by TGF-, which is lost following an epithelial to mesenchymal transition
We demonstrate that a gradual down-regulation of Smad3 during the process of epithelial to mesenchymal transition (EMT) is sufficient for the cells to lose their ability to undergo growth arrest in response to TGF-
Summary
Transforming growth factor- (TGF-)1 plays two rather paradoxical roles in cancer [1,2,3]. Long Term Activation of Raf Leads to Down-regulation of Smad3 Expression—To understand how MDCK cells alter their response to exogenous TGF- during the process of Rafinduced EMT, we examined the functions of the Smads in cells expressing ⌬Raf-ER but in its inactive form and in the same cells treated with 4HT for different times to activate the ⌬RafER.
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