Ski proto-oncogene in development and oncogenesis

发育和肿瘤发生中的滑雪原癌基因

• 批准号: 7281690
• 负责人: KUNXIN LUO
• 金额: $ 23.44万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7281690
• 关键词: Affect; Binding; Biological Assay; Biological Models; Cell Cycle Arrest; Cell Nucleus; Cell Surface Receptors; Cells; Complex; Development; Embryo; Embryonic Development; Epithelial; Epithelial Cells; Funding; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Growth; Human; In Vitro; Knock-in Mouse; Malignant - descriptor; Mediating; Mediator of activation protein; Microarray Analysis; Molecular; Molecular Profiling; Morphogenesis; Mouse Strains; Mus; Muscle; Muscle Development; Neuronal Differentiation; Nuclear; Nuclear Family; Nuclear Translocation; Oncogene Proteins; Oncogenes; Oncogenic; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Process; Protein Overexpression; Proto-Oncogenes; Regulation; Repression; Role; Signal Pathway; Signal Transduction; Skeletal system; Skiing; Smad Proteins; Smad protein; Testing; Transcriptional Activation; Transforming Growth Factor beta; Transforming Growth Factors; Tumor Suppressor Proteins; bone morphogenic protein; cancer cell; carcinogenesis; cell growth; cell growth regulation; craniofacial; cytokine; design; in vivo; in vivo Model; inhibitor/antagonist; member; metaplastic cell transformation; mutant; tumorigenesis

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.

描述（由申请人提供）：细胞因子的转化生长因子-b (TGFb) 超家族，包括 TGFbeta 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 TGFbeta 和 BMP 信号传导的关键介质。在被 TGFbeta 或 BMP 受体激酶磷酸化和激活后，Smad 蛋白易位到细胞核中并调节 TGFbeta 或 BMP 响应基因的转录。在细胞核中，Smad 的活性受到正向和负向细胞辅助因子的严格调节。 P.I.先前已鉴定出核原癌蛋白 Ski 是 TGFb 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，特别是与其与 Smad 蛋白相互作用的能力相关。 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。 P.I.研究表明，在细胞核中，Ski 与 TGFbeta 以及 BMP 特异性 Smad 复合物相互作用，并抑制它们激活 TGFbeta 和 BMP 靶基因转录的能力。由于 TGFbeta-Smad 通路已被证明是重要的肿瘤抑制通路，并且 BMP 是胚胎发育的关键调节因子，因此我们假设与 Smad 蛋白相互作用的能力是 Ski 的转化活性及其调节肌肉的能力所必需的。和神经元分化。本研究旨在检验这一假设，对哺乳动物上皮癌变和胚胎发育过程中Ski-Smad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）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。