Ski proto-oncogene in development and oncogenesis

描述（由申请人提供）：细胞因子的转化生长因子-b（TGF β）超家族，包括TGF β和骨形态发生蛋白（BMP），在细胞生长和脊椎动物发育的调节中发挥重要作用。Smad蛋白是TGF β和BMP信号传导的关键介质。在TGF β或BMP受体激酶的磷酸化和活化后，Smad蛋白易位到细胞核中并调节TGF β或BMP应答基因的转录。在细胞核中，Smads的活性受到正性和负性细胞辅因子的严格调节。私家侦探先前已经鉴定了核原癌蛋白Ski作为TGF β和BMP信号传导的重要负调节因子。该提案的长期目标是了解Ski癌蛋白在发育和转化中的功能，特别是与Smad蛋白相互作用的能力。 Ski是一种独特的癌蛋白，因为它可以诱导致癌转化以及肌肉前体的终末分化。然而，Ski调节这两个过程的机制尚未确定。私家侦探已经表明，在细胞核中，Ski与TGF β以及BMP特异性Smad复合物相互作用，并抑制它们激活TGF β和BMP靶基因转录的能力。由于TGF β-Smad途径已被证明是一个重要的肿瘤抑制途径和骨形成蛋白是胚胎发育的关键调节因子，我们假设与Smad蛋白相互作用的能力是Ski的转化活性及其调节肌肉和神经元分化的能力所必需的。本研究旨在验证这一假说，并对Ski-Smad在哺乳动物上皮癌变和胚胎发育过程中的相互作用进行详细的功能分析，并研究Ski功能的分子机制。具体目标是：1）Ski在致癌转化中的作用分析; 2）Ski诱导基因的微阵列分析; 3）Ski-Smad相互作用在胚胎发育中的作用分析。这些研究将有助于从机制上理解Ski癌蛋白的功能以及Ski和Ski-Smad的作用。 哺乳动物上皮癌变和胚胎发育中的相互作用。

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.