Mutant p53 attenuates the SMAD-dependent transforming growth factor β1 (TGF-β1) signaling pathway by repressing the expression of TGF-β receptor type II

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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.

Original languageAmerican English
Pages (from-to)8228-8242
Number of pages15
JournalMolecular and Cellular Biology
Volume27
Issue number23
DOIs
StatePublished - Dec 2007
Externally publishedYes

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