Differential regulation of tgf-β signaling through smad2, smad3 and smad4

ABSTRACT Smad transcription factors mediate the growth inhibitory effect of transforming growth factor-_β_ (TGF-_β_) in many cell types. Mutational inactivation of Smads has been correlated

with loss of responsiveness to TGF-_β_-mediated signal transduction. In this study, we compare the contribution of individual Smads to TGF-_β_-induced growth inhibition and endogenous gene

expression in isogenic cellular backgrounds. Smad2, Smad3 and Smad4 expression were selectively inhibited in differentiation-competent cells by using improved antisense molecules. We found

that TGF-_β_ mediates its inhibitory effect on HaCaT keratinocyte cell growth predominantly through Smad3. Inhibition of Smad3 expression was sufficient to interfere with TGF-_β_-induced

cell cycle arrest and to induce or suppress endogenous cell cycle regulators. Inhibition of Smad4 expression exhibited a partial effect, whereas inhibition of Smad2 expression had no effect.

By gene expression profiling, we identified TGF-_β_-dependent genes that are differentially regulated by Smad2 and Smad3 under regular growth conditions on a genome-wide scale. We show that

Smad2, Smad3 and Smad4 contribute to the regulation of TGF-_β_ responses to varying extents, and demonstrate, in addition, that these Smads exhibit distinct roles in different cell types.

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are grateful to Oliver Keil for preparing transfection vehicles. We thank Carmen Gruber, Mike Ziegner and Frank Tiemann for help with the flow cytometer. We thank Mike Engle, Ralf Saegebarth

and Steve Lack for expert bioinformatic support. We are grateful to Klaus Giese, Frank Gebhardt, Frauke Leenders and especially Bert Pronk and Lisa Molz for critically reading the

manuscript. This study was supported by a grant from the Bundesministerium für Forschung und Technologie (No. 0311830/9). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * atugen AG,

Robert-Roessle-Strasse 10, Otto Warburg Hause (No. 80), Berlin, 13125, Germany Anny Kretschmer, Kristin Moepert, Sibylle Dames, Maria Sternberger, Joerg Kaufmann & Anke Klippel Authors *

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Kretschmer, A., Moepert, K., Dames, S. _et al._ Differential regulation of TGF-_β_ signaling through Smad2, Smad3 and Smad4. _Oncogene_ 22, 6748–6763 (2003).

https://doi.org/10.1038/sj.onc.1206791 Download citation * Received: 09 April 2003 * Revised: 14 May 2003 * Accepted: 14 May 2003 * Published: 02 October 2003 * Issue Date: 02 October 2003 *

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * Smad * TGF-_β_ * tumor suppressor * micro-array