INTEGRIN AND VIRAL TRANSFORMATION

整合素和病毒转化

• 批准号: 2700423
• 负责人: DAVID E BOETTIGER
• 金额: $ 28.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2700423
• 关键词: Rous sarcoma virus; acidity /alkalinity; biological signal transduction; cell adhesion; cell cycle; cell transformation; chick embryo; contact inhibition; extracellular matrix; extracellular matrix proteins; fibroblasts; gene expression; growth factor; guanine nucleotide binding protein; immunofluorescence technique; integrins; mitogens; monoclonal antibody; northern blottings; oncogenes; phosphorylation; receptor binding; regulatory gene; synchronous cell division; tissue /cell culture

Transformation of cells by Rous sarcoma virus is dependent on the expression of virus encoded src gene. Experiments using microinjection or co-expression of dominant negative ras or raf genes has suggested that the mechanism by which v-src transforms cells involves ras and raf mediated signal transduction. But these conditions not only suppress v-src induced cell transformation, they also suppress normal cell proliferation. An alternative view is that v-src functions through its interaction with molecules involved in cell adhesion and determination of cell shape. The difficulty with this view is that there is little functional data to support it and the potential mechanisms by which cell adhesion may alter cell gene expression and cell proliferation are at a very early stage of development. The objective of this proposal is to fill this void and test the hypothesis that v-src operates by interfering with normal cell signaling pathways which are linked to cell adhesion and particularly to integrin family receptors. To test this proposition, we will reexamine two old model systems for cell transformation from the perspective of a possible link between v-src dependent cell proliferation and v-src mediated modulation of integrin mediated cell adhesion. (i) Deprivation of serum causes cells to arrest in Go. Activation of v-src in the arrested cells induces cell proliferation. The role of integrins in the establishment of the quiescent state and the potential requirement for integrin modulation to reinitiate cell proliferation will be tested. Does v-src induced proliferation depend on its effect to weaken integrin extracellular matrix links? (ii) Transformed fibroblasts are able to proliferate in suspension whereas normal fibroblasts require an adhesive substrate. The role of integrins in supplying this adhesion signal and the possibility that v-src disrupts this signal will be examined using cell cycle analysis, functional analysis of adhesion requirements and genetic manipulation.

通过ROUS肉瘤病毒对细胞的转化取决于 病毒编码的SRC基因的表达。 使用显微注射或 主要的负RA或RAF基因的共同表达表明 V-SRC转化细胞涉及RA和RAF介导的机制 信号转导。 但是这些条件不仅抑制V-SRC引起的 细胞转化，它们还抑制了正常的细胞增殖。 一个 替代视图是V-SRC通过与 涉及细胞粘附和细胞形状测定的分子。 这 这种观点的困难是，几乎没有功能数据 支持它及其细胞粘附可能改变的潜在机制 细胞基因表达和细胞增殖处于很早的阶段 发展。 该提议的目的是填补这一空白并进行测试 V-SRC通过干扰正常细胞的假设 信号通路与细胞粘附有关，尤其是 整合素家族受体。 为了测试此主张，我们将重新检查两个旧模型系统 从V-SRC之间可能链接的角度进行转换 整合素的依赖性细胞增殖和V-SRC介导的调节 介导的细胞粘附。 （i）剥夺血清会导致细胞停滞 在去。在被捕细胞中激活V-SRC会诱导细胞 增殖。 整联蛋白在静态的建立中的作用 状态和整联蛋白调制的潜在要求 细胞增殖将进行测试。 V-SRC诱导的增殖是否取决于 关于削弱整合素外基质链路的影响？ （ii） 转化的成纤维细胞能够在悬浮液中增殖 正常的成纤维细胞需要粘合剂底物。 整合素的作用 在提供此粘附信号以及V-SRC中断的可能性时 该信号将使用细胞周期分析，功能分析检查 粘附要求和遗传操作。