Crosstalk between oncoprotein Ski and TGF-B signaling

描述（由申请人提供）：Ski属于原癌蛋白家族，其在过表达时转化禽类胚胎成纤维细胞。它是一种能够以环境依赖性方式激活或抑制基因转录的核蛋白。我们已经表明，Ski可以与Smad 3相互作用，Smad 3是转化生长因子β（TGF-β）信号传导的细胞内介质。TGF-β有效地阻断细胞增殖;因此TGF-β信号传导的组分是肿瘤抑制剂的候选者。通过癌基因的突变或激活使TGF-β信号转导物失活是人类癌症发生中的常见事件。我们已经发现，响应于TGF-β信号传导，Ski与Samd 3/4形成复合物。所得到的蛋白质复合物不妨碍Smad的DNA结合，但是通过募集转录辅阻遏物来阻断由Smad介导的转录。过度表达Ski的上皮细胞对TGF-β的生长抑制具有抗性，这可能涉及Ski的转化机制。最近，我们发现Ski在哺乳动物细胞中的过表达可导致细胞周期和增殖的调节受损。此外，Ski似乎废除了p300的功能，p300是另一种重要的肿瘤抑制蛋白，作为多种细胞信号传导途径的整合剂。在这里，我们建议，以确定细胞周期和增殖调节滑雪和它的能力与Smad相互作用之间的关系。我们还将确定Ski调控p300的分子机制，并探索Ski在细胞分化中的作用。这些研究将导致更好地了解Ski调节细胞生长和分化的能力以及TGF-β信号传导机制的细胞和分子背景，并最终帮助我们了解肿瘤发生的分子机制。

DESCRIPTION (provided by applicant): Ski belongs to a family of protooncoproteins that transform avian embryo fibroblasts upon overexpression. It is a nuclear protein capable of activating or repressing gene transcription in a context dependent manner. We have shown that Ski can interact with Smad3, an intracellular mediator of transforming growth factor Beta (TGF-Beta) signaling. TGF-Beta potently blocks cellular proliferation; thus components of TGF-Beta signaling are candidates of tumor suppressors. Inactivation of TGF-Beta signal transducers through mutations or activation of oncogenes occurs as a frequent event in the genesis of human cancer. We have found that in response to TGF-Beta signaling, Ski forms a complex with Samd3/4. The resultant protein complex does not impede Smad's DNA binding, however blocks transcription mediated by Smads through recruitment of transcription corepressors. Epithelial cells overexpressing Ski are resistant to growth inhibition by TGF-B, which potentially implicates Ski's mechanism of transformation. More recently, we have found that overexpression of Ski in mammalian cells can lead to impaired regulation of cell cycle and proliferation. In addition, Ski appears to abrogate function of p300, another important tumor suppressor protein acting as an integrator of variety of cellular signaling pathways. Here we propose to determine the relationship between cell cycle and proliferation regulation by Ski and its ability to interact with Smad. We will also determine the molecular mechanisms underlying the regulation of p300 by Ski, and explore the role of Ski in cellular differentiation. These studies will lead to a better understanding of the cellular and molecular contexts for Ski's ability to regulate cell growth and differentiation as well as mechanisms of TGF-Beta signaling, and ultimately will help us to understand molecular mechanisms of tumorigenesis in general.