Transforming growth factor-? (TGF?) regulates a wide variety of normal cellular processes including proliferation, survival, cell-matrix interaction, differentiation and plays a complex role during mammalian tumorigenesis. SnoN is a potent negative regulator of TGF? signaling through binding to and antagonizing the activity of the Smad proteins. It is a member of the Ski family of classically defined proto-oncogenes that when overexpressed, induces transformation of chicken and quail embryo fibroblasts. It is expressed in all adult cells and tissues at a low level but its expression is altered (up- or down-regulated) in many human cancer cells. Previous studies related to SnoN function mostly focused on its ability to promote oncogenic transformation in chicken embryo cells. Virtually nothing is known about its function in normal mammalian epithelial cells, and its role in mammalian tumorigenesis has not been well defined. The long-term goal of this proposal is to understand the function of SnoN and the SnoN/Smad interaction in regulation of cell proliferation, survival and senescence as well as mammalian tumorigenesis and to determine the molecular mechanisms underlying these processes. We will employ the mouse embryo fibroblasts (MEF) and MCF10A normal human mammary epithelial cell line to investigate the function of SnoN in normal mammalian cells. In an effort to determine the physiological significance of the SnoN/Smad interaction, we have isolated MEF from a strain of knock-in mice that express a mutant SnoN deficient in binding to the Smad proteins. These MEF cells display enhanced sensitivity to apoptotic stimuli and more interestingly, premature senescence, indicating that the SnoN/Smad interaction may regulate the apoptosis and senescence responses. We have also employed small-interference RNA approach in MCF10A cells and showed that SnoN promotes epithelial survival in a basement membrane-dependent manner. In this proposal, we would like to test the hypothesis that SnoN possess both anti-oncogenic and pro-oncogenic activities through regulation of cell senescence, survival and proliferation in both Smad-dependent and Smad-independent manner.
The specific aims are: 1) To determine the molecular mechanism by which SnoN regulates cell senescence;2) To determine whether SnoN can function as a tumor suppressor through its ability to induce premature senescence;3) To determine the function of SnoN in normal human epithelial cells. These studies will allow us to understand the function of SnoN in normal mammalian cells and how deregulation of these activities facilitates tumorigenesis.

Public Health Relevance

SnoN is a potent negative regulator of transforming growth factor-? (TGF-?) signaling, which play important but complex roles during mammalian tumorigenesis. It regulates many aspects of cellular functions including proliferation, differentiation, senescence and motility and contains both oncogenic and anti-oncogenic activities. Identification of the signaling pathways mediating each of these activities and deciphering the specificity of these pathways are crucial not only for understanding the mechanisms controlling malignant progression but also for development of novel cancer therapy that specifically targets the oncogenic activity of SnoN while preserving its anti-oncogenic activity.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Molecular Oncogenesis Study Section (MONC)
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Salnikow, Konstantin
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University of California Berkeley
Schools of Arts and Sciences
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Pan, Deng; Zhu, Qingwei; Conboy, Michael J et al. (2012) SnoN activates p53 directly to regulate aging and tumorigenesis. Aging Cell 11:902-911
Zhu, Qingwei; Luo, Kunxin (2012) SnoN in regulation of embryonic development and tissue morphogenesis. FEBS Lett 586:1971-6
Jahchan, Nadine S; You, Young-Hyun; Muller, William J et al. (2010) Transforming growth factor-beta regulator SnoN modulates mammary gland branching morphogenesis, postlactational involution, and mammary tumorigenesis. Cancer Res 70:4204-13
Jahchan, Nadine S; Luo, Kunxin (2010) SnoN in mammalian development, function and diseases. Curr Opin Pharmacol 10:670-5
Deheuninck, Julien; Luo, Kunxin (2009) Ski and SnoN, potent negative regulators of TGF-beta signaling. Cell Res 19:47-57
Pan, Deng; Zhu, Qingwei; Luo, Kunxin (2009) SnoN functions as a tumour suppressor by inducing premature senescence. EMBO J 28:3500-13
Zhu, Qingwei; Krakowski, Ariel R; Dunham, Elizabeth E et al. (2007) Dual role of SnoN in mammalian tumorigenesis. Mol Cell Biol 27:324-39
Krakowski, Ariel R; Laboureau, Julien; Mauviel, Alain et al. (2005) Cytoplasmic SnoN in normal tissues and nonmalignant cells antagonizes TGF-beta signaling by sequestration of the Smad proteins. Proc Natl Acad Sci U S A 102:12437-42
Zhu, Qingwei; Pearson-White, Sonia; Luo, Kunxin (2005) Requirement for the SnoN oncoprotein in transforming growth factor beta-induced oncogenic transformation of fibroblast cells. Mol Cell Biol 25:10731-44
Pan, Deng; Estevez-Salmeron, Luis D; Stroschein, Shannon L et al. (2005) The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the transforming growth factor-{beta} superfamily of cytokines. J Biol Chem 280:15992-6001

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