GROWTH CONTROL BY THE IGF-1 RECEPTOR

IGF-1 受体的生长控制

• 批准号: 6499784
• 负责人: RENATO Luigi BASERGA
• 金额: $ 29.68万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6499784
• 关键词: cell cycle; cell proliferation; cell transformation; growth factor receptors; insulinlike growth factor; platelet derived growth factor; proliferating cell nuclear antigen; protein structure function; receptor binding; receptor expression; tissue /cell culture; yeast two hybrid system

This project is centered on the insulin-like growth factor type 1 receptor (IGF-1R), and its ability to regulate cellular proliferation and transformation. It is based on substantial evidence that an overexpressed IGF-IR is transforming, while, on the contrary, a decreased expression or functional impairment lead to reversal of the transformed phenotype in several cell types. Furthermore, the mitogenic and transforming functions can be localized to different domains of the IGF-IR, and a number of experiments indicate that other substrates of the receptor (besides the known ones, IRS-1, IRS-2 and Shc) must be involved. The project will endeavor: 1) to search for new substrates of the IGF- IR, especially of its C-terminus, where the transforming function is localized, by the yeast two-hybrid system; 2) to analyze the biological functions of one of these new substrates, Grb10, identified through the yeast two-hybrid system. Grb10 binds to the IGR-IR but not to a receptor truncated in the C-terminus: 3) to investigate in depth a novel finding, that IGF-II stimulates mitogenesis through the insulin receptor; and 4) to explore the quantitative aspects of IGR-IR action, and its relation to PDGE stimulation. The findings of our laboratory that mitogenesis and transformation can be dissociated at a molecular level, and that several strategies targeted against the IGF-1R (antisense plasmids, dominant negatives, antibodies) inhibit transformation and tumorigenesis clearly point out the relevance of these studies to the cancer problem, both from a basic point of view and from a practical point of view.

该项目以 1 型胰岛素样生长因子为中心 受体（IGF-1R）及其调节细胞增殖和 转变。 它基于大量证据表明 过度表达的 IGF-IR 正在发生转变，而相反， 表达减少或功能障碍导致逆转 几种细胞类型中的转化表型。 此外，促有丝分裂 并且转换函数可以本地化到不同的域 IGF-IR 和大量实验表明，其他底物 受体（除了已知的 IRS-1、IRS-2 和 Shc 之外）必须是 涉及。 该项目将致力于：1）寻找IGF-的新底物 IR，尤其是其 C 末端，其中变换函数为 通过酵母双杂交系统进行本地化； 2) 生物学分析 这些新底物之一 Grb10 的功能，通过 酵母二杂交系统。 Grb10 与 IGR-IR 结合，但不与 C 端截短的受体：3) 深入研究一种新颖的 发现 IGF-II 通过胰岛素受体刺激有丝分裂发生； 4) 探索 IGR-IR 作用的定量方面及其 与 PDGE 刺激的关系。 我们实验室的研究结果表明有丝分裂和转化可以 在分子水平上解离，并且有几种策略针对 针对 IGF-1R（反义质粒、显性失活、抗体） 抑制转化和肿瘤发生清楚地指出了相关性 这些研究都从基本角度对癌症问题进行了研究 并且从实际的角度来看。