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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Arginine / genetics
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Gene Expression Regulation, Neoplastic / drug effects
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Genes, Reporter
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Histidine / genetics
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Humans
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Matrix Metalloproteinase 2 / biosynthesis
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Matrix Metalloproteinase 9 / biosynthesis
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mutant Proteins / metabolism*
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Phosphorylation
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Protein Binding / drug effects
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Protein Serine-Threonine Kinases / metabolism*
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Protein Transport / drug effects
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Proto-Oncogene Proteins c-myc / metabolism
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / metabolism*
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Repressor Proteins / metabolism*
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Signal Transduction / drug effects*
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Smad Proteins / metabolism*
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Transforming Growth Factor beta1 / pharmacology*
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Tumor Suppressor Protein p53 / metabolism*
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Wound Healing / drug effects
Substances
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Mutant Proteins
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Proto-Oncogene Proteins c-myc
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Receptors, Transforming Growth Factor beta
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Repressor Proteins
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Smad Proteins
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Transforming Growth Factor beta1
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Tumor Suppressor Protein p53
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Histidine
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Arginine
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9