Ski proto-oncogene in development and oncognesis

发育和致癌中的滑雪原癌基因

• 批准号: 7118003
• 负责人: KUNXIN LUO
• 金额: $ 0.61万
• 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/7118003
• 关键词: biological signal transduction; bone morphogenetic proteins; carcinogenesis; cell growth regulation; developmental genetics; gene expression; genetic manipulation; genetic regulation; genetically modified animals; laboratory mouse; mammalian embryology; microarray technology; molecular oncology; neoplasm /cancer genetics; neoplastic transformation; oncoproteins; protein protein interaction; protein structure function; protooncogene; transcription factor; transforming growth factors

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），包括TGFBETAS和骨形态发生蛋白（BMP），在调节细胞生长和脊椎动物发育方面起着重要作用。 SMAD蛋白是TGFBETA和BMP信号传导的关键介体。 TGFBETA或BMP受体激酶的磷酸化和激活后，SMAD蛋白转移到细胞核中并调节TGFBETA或BMP反应性基因的转录。在细胞核中，SMAD的活性受正阳性和负细胞共同因素的严格调节。 P.I.先前已经将核原抗蛋白蛋白滑雪物鉴定为TGFB和BMP信号传导的重要负调节剂。该建议的长期目标是了解滑雪蛋白在发育和转化中的功能，尤其是与其与SMAD蛋白质相互作用的能力有关。 滑雪是一种独特的癌蛋白，它可以诱导肌肉前体的致癌转化和末端分化。但是，尚未定义滑雪调节这两个过程的机制。 P.I.已经表明，在细胞核中，滑雪与TGFBETA-以及BMP-特异性SMAD复合物相互作用，并抑制其激活TGFBETA和BMP靶基因转录的能力。由于TGFBETA-SMAD途径已被证明是重要的肿瘤抑制途径，而BMP是关键的调节剂或胚胎发育，我们假设与SMAD蛋白相互作用的能力对于SKI的转化及其调节肌肉和神经元分化的能力都是必需的。该建议旨在检验这一假设，并在哺乳动物上皮致癌期和胚胎发育过程中对滑雪SMAD相互作用进行详细的功能分析，并研究滑雪功能的分子机制。具体目的是：1）滑雪在致癌转化中的作用分析； 2）滑雪诱导基因的微阵列分析； 3）分析滑雪 - SMAD相互作用在胚胎发育中的作用。这些研究将允许对滑雪蛋白的功能以及滑雪和滑雪 - 摩尔德相互作用在哺乳动物上皮癌和胚胎发育中的作用。