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Molecular and Cellular Biology, December 2007, p. 8228-8242, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00374-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor ß1 (TGF-ß1) Signaling Pathway by Repressing the Expression of TGF-ß Receptor Type II{triangledown}

Eyal Kalo,1 Yosef Buganim,1 Keren E. Shapira,2 Hilla Besserglick,1 Naomi Goldfinger,1 Lilach Weisz,1 Perry Stambolsky,1 Yoav I. Henis,2 and Varda Rotter1*

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel,1 Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel2

Received 1 March 2007/ Returned for modification 11 May 2007/ Accepted 11 September 2007

Both transforming growth factor beta (TGF-ß) and p53 have been shown to control normal cell growth. Acquired mutations either in the TGF-ß signaling pathway or in the p53 protein were shown to induce malignant transformation. Recently, cross talk between wild-type p53 and the TGF-ß pathway was observed. The notion that mutant p53 interferes with the wild-type p53-induced pathway and acts by a "gain-of-function" mechanism prompted us to investigate the effect of mutant p53 on the TGF-ß-induced pathway. In this study, we show that cells expressing mutant p53 lost their sensitivity to TGF-ß1, as observed by less cell migration and a reduction in wound healing. We found that mutant p53 attenuates TGF-ß1 signaling. This was exhibited by a reduction in SMAD2/3 phosphorylation and an inhibition of both the formation of SMAD2/SMAD4 complexes and the translocation of SMAD4 to the cell nucleus. Furthermore, we found that mutant p53 attenuates the TGF-ß1-induced transcription activity of SMAD2/3 proteins. In searching for the mechanism that underlies this attenuation, we found that mutant p53 reduces the expression of TGF-ß receptor type II. These data provide important insights into the molecular mechanisms that underlie mutant p53 "gain of function" pertaining to the TGF-ß signaling pathway.

* Corresponding author. Mailing address: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel. Phone: 972-8-934 4501. Fax: 972-8-946 5265. E-mail: varda.rotter{at}weizmann.ac.il

{triangledown} Published ahead of print on 17 September 2007.

Molecular and Cellular Biology, December 2007, p. 8228-8242, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00374-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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