Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor β1 (TGF-β1) Signaling Pathway by Repressing the Expression of TGF-β Receptor Type II

Abstract

Both transforming growth factor beta (TGF-β) and p53 have been shown to control normal cell growth. Acquired mutations either in the TGF-β signaling pathway or in the p53 protein were shown to induce malignant transformation. Recently, cross talk between wild-type p53 and the TGF-β 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-β-induced pathway. In this study, we show that cells expressing mutant p53 lost their sensitivity to TGF-β1, as observed by less cell migration and a reduction in wound healing. We found that mutant p53 attenuates TGF-β1 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-β1-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-β receptor type II. These data provide important insights into the molecular mechanisms that underlie mutant p53 “gain of function” pertaining to the TGF-β signaling pathway.

This research was supported by a Center of Excellence grant from the Flight Attendant Medical Research Institute (FAMRI), by EC FP6 grant LSHC-CT-2004-503576, by funding from the Yad Abraham Center for Cancer Diagnosis and Therapy (to V.R.), and by a grant from the Israel Science Foundation (grant 185/05) (to Y.I.H.). V.R. is the incumbent of the Norman and Helen Asher Professorial Chair of Cancer Research at the Weizmann Institute of Science. Y.I.H. is the incumbent of the Zalman Weinberg Chair in Cell Biology at Tel Aviv University.

This publication reflects the authors’ views, which do not necessarily reflect those of the European Community (EC). The EC is not liable for any use that may be made of the information contained herein.

We thank P. Knaus for the kind gift of luciferase plasmid constructs.