Abstract
The expression of 14-3-3 proteins is dysregulated in various types of cancer. This study was undertaken to investigate the effects of 14-3-3 ζ and 14-3-3 σ on cell growth inhibition mediated by transforming growth factor-beta 1 (TGF-β1). Mouse mammary epithelial cells (Eph4) that are transformed with oncogenic c-H-Ras (EpRas) and no longer sensitive to TGF-β1-mediated growth inhibition displayed increased expression of 14-3-3 ζ and decreased expression of 14-3-3 σ compared with parental Eph4 cells. Using small interfering RNA-mediated knockdown and overexpression of 14-3-3 σ or 14-3-3 ζ, we showed that 14-3-3 σ is required for TGF-β1-mediated growth inhibition whereas 14-3-3 ζ negatively modulates this growth inhibitory response. Notably, overexpression of 14-3-3 ζ increased the level of Smad3 protein that is phosphorylated at linker regions and cannot mediate the TGF-β1 growth inhibitory response. Consistent with this finding, mutation of the 14-3-3 ζ phosphorylation sites in Smad3 markedly reduced the 14-3-3 ζ-mediated inhibition of TGF-β1-induced p15 promoter-reporter activity and cell cycle arrest, suggesting that these residues are critical targets of 14-3-3 ζ in the suppression of TGF-β1-mediated growth. Taken together, our findings indicate that dysregulation of 14-3-3 σ or 14-3-3 ζ contributes to TGF-β1 resistance in cancer cells.
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Hong, HY., Jeon, WK., Bae, EJ. et al. 14-3-3 sigma and 14-3-3 zeta plays an opposite role in cell growth inhibition mediated by transforming growth factor-beta 1. Mol Cells 29, 305–309 (2010). https://doi.org/10.1007/s10059-010-0037-8
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DOI: https://doi.org/10.1007/s10059-010-0037-8