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Start Over Author "Lasfar A" Journal pigment cell & melanoma research
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3. Constitutive Smad linker phosphorylation in melanoma: a mechanism of resistance to transforming growth factor-β-mediated growth inhibition

Author

Joseph L.-K. Chan, Wenjin Chen, James S. Goydos, Karine A. Cohen-Solal, Kim T. Merrigan, Fang Liu, Ahmed Lasfar, Michael Reiss, and David J. Foran

Subjects
integumentary system, Dermatology, Transfection, SMAD, Transforming growth factor beta, Biology, Molecular biology, General Biochemistry, Genetics and Molecular Biology, chemistry.chemical_compound, Oncology, chemistry, Cyclin-dependent kinase, biology.protein, Phosphorylation, Smad2 Protein, biological phenomena, cell phenomena, and immunity, Growth inhibition, Transforming growth factor
Abstract

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 p15INK4B and p21WAF1, 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.

Published
2011

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