The Role of SnoN and Ski in Mammary Epithelial Cell Transformation

Abstract : The transforming growth factor-beta (TGFB), signaling through the Smad proteins, regulates a wide variety of cellular processes including proliferation, survival, cell-matrix interaction, differentiation and plays a complex role in mammalian tumorigenesis. SnoN and Ski are critical negative regulators of TGFB signaling by binding to and repressing the activities of the Smad proteins. Our previous work have shown that SnoN and Ski expression is often elevated in breast cancer cells and they play both pro-oncogenic and anti-oncogenic functions in breast cancer development. In this study, we explored the anti-oncogenic activity of SnoN and showed that high levels of SnoN induced premature senescence in mammalian epithelial cells. SnoN interacted with the Promyelocytic leukemia (PML) protein and was recruited to the PML nuclear bodies where it stabilizes p53, leading to premature senescence. Furthermore, overexpression of SnoN inhibits oncogenic transformation induced by Ras and Myc in vitro and significantly blocks papilloma development in vivo in a carcinogen-induced skin tumorigenesis model. The few papillomas that were developed displayed high levels of senescence and spontaneously regressed. Our study has revealed a novel Smad-independent pathway of SnoN function that mediates its anti-oncogenic activity.