Crosstalk between oncoprotein Ski and TGF-B signaling

描述（由申请人提供）：Ski属于一个原癌蛋白家族，该家族通过过度表达转化禽类胚胎成纤维细胞。它是一种核蛋白，能够以上下文依赖的方式激活或抑制基因转录。我们已经证明Ski可以与Smad3相互作用，Smad3是一种转化生长因子β (tgf - β)信号的细胞内介质。tgf - β能有效阻断细胞增殖；因此tgf - β信号的成分是肿瘤抑制因子的候选成分。tgf - β信号转导通过致癌基因的突变或激活而失活，是人类癌症发生过程中经常发生的事件。我们发现，在对tgf - β信号的反应中，Ski与Samd3/4形成复合物。由此产生的蛋白复合物不会阻碍Smad的DNA结合，但会通过募集转录辅抑制子阻断Smad介导的转录。过表达Ski的上皮细胞对TGF-B的生长抑制具有抗性，这可能与Ski的转化机制有关。最近，我们发现Ski在哺乳动物细胞中的过度表达会导致细胞周期和增殖的调节受损。此外，Ski似乎取消了p300的功能，p300是另一种重要的肿瘤抑制蛋白，作为多种细胞信号通路的整合者。在这里，我们提出确定细胞周期和增殖调节的Ski及其与Smad相互作用的能力之间的关系。我们还将确定Ski调控p300的分子机制，并探讨Ski在细胞分化中的作用。这些研究将使我们更好地了解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.