14-3-3 Sigma and 14-3-3 Zeta Plays an Opposite Role in Cell Growth Inhibition Mediated by Transforming Growth Factor-Beta 1

• Published in: Molecules and cells Vol. 29; no. 3; pp. 305 - 309
• Main Authors: Hong, H.Y., Kangwon National University, Chuncheon, Republic of Korea, Jeon, W.K., Kangwon National University, Chuncheon, Republic of Korea, Bae, E.J., Gachon University of Medicine and Science, Incheon, Republic of Korea, Kim, S.T., Gachon University of Medicine and Science, Incheon, Republic of Korea, Lee, H.J., Gachon University of Medicine and Science, Incheon, Republic of Korea, Kim, S.J., Gachon University of Medicine and Science, Incheon, Republic of Korea, Kim, B.C., Kangwon National University, Chuncheon, Republic of Korea
• Format: Journal Article
• Language: English
• Published: Springer Korean Society for Molecular and Cellular Biology 01.03.2010; 한국분자세포생물학회
• Subjects: 14-3-3 Proteins - physiology; Animals; Binding Sites; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cell Biology; Cell Cycle; Cell Division - drug effects; cell growth inhibition; Cell Line, Transformed; Cell Transformation, Viral; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Epithelial Cells - cytology; Epithelial Cells - drug effects; FACTEUR DE CROISSANCE TRANSFORMANT; FACTOR DE CRECIMIENTO TRANSFORMANTE; Female; Gene Knockdown Techniques; Genes, ras; Life Sciences; Mammary Glands, Animal - cytology; Mice; Phosphorylation; phosphorylation of Smad3 linker region; Protein Processing, Post-Translational; RNA Interference; RNA, Small Interfering - pharmacology; Smad3 Protein - genetics; Smad3 Protein - metabolism; TRANSFORMING GROWTH FACTOR; Transforming Growth Factor beta1 - antagonists & inhibitors; Transforming Growth Factor beta1 - physiology; 생물학; phosphorylation of Smad3 linker region; 14-3-3 σ; cell growth inhibition; TGF-β1; 14-3-3 ζ
• ISSN: 1016-8478; 0219-1032
• DOI: 10.1007/s10059-010-0037-8

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.