GROWTH CONTROL BY THE IGF-1 RECEPTOR

该项目以胰岛素样生长因子1为中心。 受体(IGF-1R)及其调节细胞增殖和 转型。它是基于大量的证据表明 过度表达的IGF-IR正在转化，而相反， 表达减少或功能障碍会导致反转 几种细胞类型的转化表型。此外，有丝分裂原 并且转换函数可以本地化到 IGF-IR和一些实验表明，其他底物 受体(除已知的IRS-1、IRS-2和Shc外)必须是 牵涉其中。 该项目将致力于：1)寻找新的IGF底物- IR，尤指其C-端，其中变换函数是 通过酵母双杂交系统进行定位；2)分析生物 其中一种新底物Grb10的功能通过 酵母双杂交系统。Grb10与IGR-IR结合，但不与 C-末端截短的受体：3)深入研究一种新的 研究发现，IGF-II通过胰岛素受体刺激有丝分裂； 4)探讨IGR-IR作用的定量方面及其 与PDGE刺激的关系。 我们实验室的发现有丝分裂和转化可以 在分子水平上被解离，并且有几种策略有针对性 抗IGF-1R(反义质粒、显性阴性、抗体) 抑制转化与肿瘤发生明确指出相关性 对癌症问题的这些研究，都是从基本的角度出发的 从实际的角度来看。

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.