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A more recent version of this article appeared on October 1, 2004
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Submitted on April 29, 2004
Revised on July 8, 2004
Accepted on August 4, 2004
Regulation of the Actin Cytoskeleton and Cell Motility in Epithelial Cells
*Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263; Department of Medicine, Vanderbilt University, Nashville, TN 37232, Research Area, Institute of Oncology "Angel H. Roffo", Buenos Aires, Argentina C1417DTB; ||Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
Monitoring Editor: Thomas Pollard
We have investigated TGF-
-mediated induction of actin stress fibers in normal and metastatic epithelial cells. We found that stress fiber formation requires de novo protein synthesis, p38Mapk and Smad signaling. We show that TGF- via Smad and p38Mapk up-regulates expression of actin-binding proteins including high molecular weight tropomyosins, 
-actinin and calponin h2. We demonstrate that, among these proteins, tropomyosins are both necessary and sufficient for TGF- induction of stress fibers. Silencing of tropomyosins with short interfering RNAs (siRNAs) blocks stress fiber assembly while ectopic expression of tropomyosins results in stress fibers. Ectopic-expression and siRNA experiments show that Smads mediate induction of tropomyosins and stress fibers. Interestingly, TGF- induction of stress fibers was not accompanied by changes in the levels of cofilin phosphorylation. TGF- induction of tropomyosins and stress fibers are significantly inhibited by Ras-ERK signaling in metastatic breast cancer cells. Inhibition of the Ras-ERK pathway restores TGF- induction of tropomyosins and stress fibers and thereby reduces cell motility. These results suggest that induction of tropomyosins and stress fibers play an essential role in TGF- control of cell motility, and the loss of this TGF- response is a critical step in the acquisition of metastatic phenotype by tumor cells.
Corresponding author.
E-mail: andrei.bakin{at}roswellpark.org
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