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Constitutive Smad linker phosphorylation in melanoma: a mechanism of resistance to transforming growth factor‐β‐mediated growth inhibition
Author(s) -
CohenSolal Karine A.,
Merrigan Kim T.,
Chan Joseph L.K.,
Goydos James S.,
Chen Wenjin,
Foran David J.,
Liu Fang,
Lasfar Ahmed,
Reiss Michael
Publication year - 2011
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/j.1755-148x.2011.00858.x
Subject(s) - phosphorylation , linker , melanoma , cancer research , transforming growth factor , cdk inhibitor , chemistry , smad , microbiology and biotechnology , transfection , cyclin dependent kinase , cell culture , cell cycle , biology , cell , biochemistry , protein kinase a , cyclin dependent kinase 2 , genetics , operating system , computer science
Summary Melanoma cells are resistant to transforming growth factor‐β (TGFβ)‐induced cell‐cycle arrest. In this study, we investigated a mechanism of resistance involving a regulatory domain, called linker region, in Smad2 and Smad3, main downstream effectors of TGFβ. Melanoma cells in culture and tumor samples exhibited constitutive Smad2 and Smad3 linker phosphorylation. Treatment of melanoma cells with the MEK1/2 inhibitor, U0126, or the two pan‐CDK and GSK3 inhibitors, Flavopiridol and R547, resulted in decreased linker phosphorylation of Smad2 and Smad3. Overexpression of the linker phosphorylation‐resistant Smad3 EPSM mutant in melanoma cells resulted in an increase in expression of p15 INK4B and p21 WAF1 , as compared with cells transfected with wild‐type (WT) Smad3. In addition, the cell numbers of EPSM Smad3‐expressing melanoma cells were significantly reduced compared with WT Smad3‐expressing cells. These results suggest that the linker phosphorylation of Smad3 contributes to the resistance of melanoma cells to TGFβ‐mediated growth inhibition.