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PMID: 17875924 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Mutant p53 attenuates the SMAD-dependent transforming growth factor beta1 (TGF-beta1) signaling pathway by repressing the expression of TGF-beta receptor type II.

Molecular and cellular biology ·Vol. 27 ·No. 23 ·2007-12-00 ·Pages 8228-42

Kalo E, Buganim Y, Shapira KE, Besserglick H, Goldfinger N, Weisz L, Stambolsky P, Henis YI, Rotter V

Abstract

Both transforming growth factor beta (TGF-beta) and p53 have been shown to control normal cell growth. Acquired mutations either in the TGF-beta signaling pathway or in the p53 protein were shown to induce malignant transformation. Recently, cross talk between wild-type p53 and the TGF-beta 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-beta-induced pathway. In this study, we show that cells expressing mutant p53 lost their sensitivity to TGF-beta1, as observed by less cell migration and a reduction in wound healing. We found that mutant p53 attenuates TGF-beta1 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-beta1-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-beta receptor type II. These data provide important insights into the molecular mechanisms that underlie mutant p53 "gain of function" pertaining to the TGF-beta signaling pathway.

MeSH Terms
Arginine/genetics Cell Line, Tumor Cell Movement/drug effects Cell Nucleus/drug effects,metabolism Gene Expression Regulation, Neoplastic/drug effects Genes, Reporter Histidine/genetics Humans Matrix Metalloproteinase 2/biosynthesis Matrix Metalloproteinase 9/biosynthesis Mitogen-Activated Protein Kinase 1/metabolism Mitogen-Activated Protein Kinase 3 Mutant Proteins/metabolism Phosphorylation Protein Binding/drug effects Protein Serine-Threonine Kinases/metabolism Protein Transport/drug effects Proto-Oncogene Proteins c-myc/metabolism Receptor, Transforming Growth Factor-beta Type I Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta/metabolism Repressor Proteins/metabolism Signal Transduction/drug effects Smad Proteins/metabolism Transforming Growth Factor beta1/pharmacology Tumor Suppressor Protein p53/metabolism Wound Healing/drug effects
Chemicals
Mutant Proteins Proto-Oncogene Proteins c-myc Receptors, Transforming Growth Factor beta Repressor Proteins Smad Proteins Transforming Growth Factor beta1 Tumor Suppressor Protein p53 Histidine Arginine Protein Serine-Threonine Kinases Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Receptor, Transforming Growth Factor-beta Type I Receptor, Transforming Growth Factor-beta Type II Matrix Metalloproteinase 2 Matrix Metalloproteinase 9
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Kalo Eyal
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Buganim Yosef
Shapira Keren E
Besserglick Hilla
Goldfinger Naomi
Weisz Lilach
Stambolsky Perry
Henis Yoav I
Rotter Varda
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.00374-07
Published
2007-12-00
Epub
2007-00-17
Pages
8228-42
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2169171
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.00374-07 PMC Full Text View journal details
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