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，其在过度表达后转化禽类胚胎成纤维细胞。它是一种核蛋白，能够以上下文相关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 是转化生长因子 Beta (TGF-Beta) 信号传导的细胞内介质。 TGF-β 有效阻止细胞增殖；因此，TGF-β信号传导成分是肿瘤抑制因子的候选者。通过突变或癌基因激活导致 TGF-β 信号转导器失活是人类癌症发生过程中的常见事件。我们发现，为了响应 TGF-Beta 信号传导，Ski 与 Samd3/4 形成复合物。由此产生的蛋白质复合物不会阻碍 Smad 的 DNA 结合，但会通过招募转录辅阻遏物来阻断 Smad 介导的转录。过度表达 Ski 的上皮细胞对 TGF-B 的生长抑制具有抵抗力，这可能暗示了 Ski 的转化机制。最近，我们发现哺乳动物细胞中 Ski 的过度表达会导致细胞周期和增殖的调节受损。此外，Ski 似乎消除了 p300 的功能，p300 是另一种重要的肿瘤抑制蛋白，充当多种细胞信号传导途径的整合者。在这里，我们建议确定 Ski 的细胞周期和增殖调节及其与 Smad 相互作用的能力之间的关系。我们还将确定Ski调节p300的分子机制，并探讨Ski在细胞分化中的作用。这些研究将有助于我们更好地了解 Ski 调节细胞生长和分化的能力的细胞和分子背景以及 TGF-Beta 信号传导机制，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.