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MBC in Press, published online ahead of print June 14, 2006
Mol. Biol. Cell 10.1091/mbc.E05-10-0990

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Submitted on October 31, 2005
Revised on May 10, 2006
Accepted on June 7, 2006

Inhibition of Transforming Growth Factor-{beta}1-induced Signaling and Epithelial to Mesenchymal Transition by the Smad-binding Peptide Aptamer Trx-SARA

Bryan M. Zhao* and F. Michael Hoffmann*{dagger}

*McArdle Laboratory for Cancer Research and {dagger}Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706

Monitoring Editor: Carl-Henrik Heldin

Overexpression of the inhibitory Smad, Smad7, is used frequently to implicate the Smad pathway in cellular responses to transforming growth factor beta (TGF-{beta}) signaling; however, Smad7 regulates several other proteins, including Cdc42, p38MAPK, and {beta}-catenin. We report an alternative approach for more specifically disrupting Smad-dependent signaling using a peptide aptamer, Trx-SARA, which comprises a rigid scaffold, the E. coli thioredoxin A protein (Trx), displaying a constrained 56 amino acid Smad binding motif from the Smad anchor for receptor activation (SARA) protein. Trx-SARA bound specifically to Smad2 and Smad3 and inhibited both TGF-{beta}-induced reporter gene expression and epithelial-to-mesenchymal transition in NMuMG murine mammary epithelial cells. In contrast to Smad7, Trx-SARA had no effect on the Smad2 or 3 phosphorylation levels induced by TGF-{beta}1. Trx-SARA was primarily localized to the nucleus and perturbed the normal cytoplasmic localization of Smad2 and 3 to a nuclear localization in the absence of TGF-{beta}1, consistent with reduced Smad nuclear export. The key mode of action of Trx-SARA was to reduce the level of Smad2 and Smad3 in complex with Smad4 after TGF-{beta}1 stimulation, a mechanism of action consistent with the preferential binding of SARA to monomeric Smad protein and Trx-SARA-mediated disruption of active Smad complexes.

Address correspondence to: F. Michael Hoffmann (fmhoffma{at}wisc.edu)




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S. K. Lim and F. M. Hoffmann
Smad4 cooperates with lymphoid enhancer-binding factor 1/T cell-specific factor to increase c-myc expression in the absence of TGF-beta signaling
PNAS, December 5, 2006; 103(49): 18580 - 18585.
[Abstract] [Full Text] [PDF]


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