GROWTH CONTROL BY THE IGF-1 RECEPTOR

本项目以胰岛素样生长因子1为中心， 受体（IGF-1 R）及其调节细胞增殖和 转型 它是基于大量证据表明， 过度表达的IGF-IR正在转化，而相反， 表达减少或功能障碍导致逆转的， 在几种细胞类型中转化表型。 此外，促有丝分裂 并且变换函数可以被局部化到 IGF-IR，和许多实验表明，其他底物的IGF-IR， 受体（除了已知的受体，IRS-1，IRS-2和Shc）必须是 涉案 该项目将奋进：1）寻找IGF的新底物， IR，特别是其C-末端，其中转化功能是 定位，通过酵母双杂交系统; 2）分析生物 这些新底物之一Grb 10的功能，通过 酵母双杂交系统 Grb 10与IGR-IR结合，但不与 受体截短的C-末端：3）深入研究一种新的 发现IGF-II通过胰岛素受体刺激有丝分裂; 和4）探索IGR-IR作用的定量方面， 与PDGE刺激有关。 我们实验室的发现，有丝分裂和转化可以 在分子水平上分离，并且有几种策略针对 针对IGF-1 R（反义质粒、显性阴性、抗体） 抑制转化和肿瘤发生清楚地指出了相关性 这些研究都是针对癌症问题的，无论是从基本的角度， 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.