Ski proto-oncogene in development and oncogenesis

描述(申请人提供)：转化生长因子-b(TGFb)超家族细胞因子，包括转化生长因子β和骨形态发生蛋白(BMPs)，在调节细胞生长和脊椎动物发育中发挥重要作用。Smad蛋白是转化生长因子β和骨形态发生蛋白信号转导的重要中介。当被TGFbeta或BMP受体激酶磷酸化和激活时，Smad蛋白移位到细胞核中，并调节TGFbeta或BMP反应基因的转录。在细胞核中，SMADs的活动受到积极和消极的细胞辅助因子的严格调控。P.I.此前已经确定，核原癌蛋白Ski是TGFb和BMP信号的重要负调控因子。这项建议的长期目标是了解Ski癌蛋白在发育和转化中的功能，特别是与其与Smad蛋白相互作用的能力。 SKI是一种独特的癌蛋白，它既可以诱导肌肉前体的致癌转化，也可以诱导肌肉前体的终末分化。然而，Ski调节这两个过程的机制还没有确定。P.I.的研究表明，在细胞核中，Ski与TGFbeta和BMP特异的Smad复合体相互作用，并抑制它们激活TGFbeta和BMP靶基因转录的能力。由于TGFbeta-Smad途径是重要的肿瘤抑制途径，BMPs是胚胎发育的关键调节因子，我们推测Ski的转化活性及其调控肌肉和神经元分化的能力都需要与Smad蛋白相互作用。本研究旨在验证这一假说，并对Ski-Smad在哺乳动物上皮细胞癌变和胚胎发育过程中的相互作用进行详细的功能分析，并探讨Ski功能的分子机制。其具体目标是：1)分析Ski在致癌转化中的作用；2)Ski诱导基因的微阵列分析；3)分析Ski-Smad相互作用在胚胎发育中的作用。这些研究将有助于从机制上了解Ski癌蛋白的功能，以及Ski和Ski-Smad相互作用在哺乳动物上皮癌发生和胚胎发育中的作用。

DESCRIPTION (provided by applicant): The transforming growth factor-b (TGFb) superfamily of cytokines, including TGFbetas and bone morphogenic proteins (BMPs), play important roles in the regulation of cell growth and vertebrate development. Smad proteins are critical mediators of TGFbeta and BMP signaling. Upon phosphorylation and activation by the TGFbeta or BMP receptor kinases, the Smad proteins translocate into the nucleus and regulate transcription of TGFbeta or BMP responsive genes. In the nucleus, the activities of the Smads are tightly regulated by both positive and negative cellular co-factors. The P.I. has previously identified a nuclear proto-oncoprotein Ski as an important negative regulator of TGFb and BMP signaling. The long-term goal of this proposal is to understand the function of Ski oncoprotein in development and transformation, in particular related to its ability to interact with the Smad proteins. Ski is a unique oncoprotein in that it can induce both oncogenic transformation as well as terminal differentiation of muscle precursors. However, the mechanism by which Ski regulates these two processes has not been defined. The P.I. has shown that in the nucleus, Ski interacts with the TGFbeta- as well as BMP- specific Smad complexes and represses their abilities to activate transcription of TGFbeta and BMP target genes. Since TGFbeta-Smad pathway has been shown to be an important tumor suppressor pathway and BMPs are critical regulators or embryonic development, we hypothesize that the ability to interact with the Smad proteins is required for both the transforming activity of Ski and its ability to modulate muscle and neuronal differentiation. This proposal is designed to test this hypothesis and carry out detailed functional analyses of the Ski-Smad interaction during mammalian epithelial carcinogenesis and embryonic development as well as to investigate the molecular mechanisms of Ski function. The specific aims are: 1) Analysis of the role of Ski in oncogenic transformation; 2) Microarray analysis of Ski inducible genes; 3) Analysis of the role of the Ski-Smad interaction in embryonic development. These studies will allow a mechanistic understanding of functions of the Ski oncoprotein as well as the role of Ski and the Ski-Smad interaction in mammalian epithelial carcinogenesis and embryonic development.