MECHANISM OF GROWTH FACTOR-INDUCED TRANSFORMATION

细胞转化机制的分析 特异性基因的转导（通过逆转录病毒感染， 转染肿瘤细胞DNA或过表达正常 细胞基因）表明，一个共同的特点是改变 在信号中特定成分的功能或调节中 转导途径介导细胞对 促有丝分裂刺激 这一长期目标 应用程序是确定参与的分子机制， 由生长因子调节改变引起的转化- 介导的信号转导途径。 一个中心因素， 促有丝分裂反应涉及蛋白激酶C的激活 (PKC)，一种钙和磷脂依赖性激酶， 被证明在增殖和增殖的途径中被激活， 分化 因此，PKC调节的改变 活性可能对生长控制具有显著影响。 事实上， PKC活性和PKC调节基因的过表达， 被称为佛宾，在成纤维细胞中已被证明可诱导 转化表型 初步证据表明， 佛宾的转化机制是通过 自分泌过程 本申请概述了一种实验性的 确定PKC或佛宾基因改变的方法 可以在特定类型的人肿瘤中鉴定表达， 转化株，以确定佛宾蛋白在 转化，以确定蛋白质的关键区域， 这是诱导转化所必需的， 确定该蛋白在PKC介导的细胞凋亡中的作用。 分化 回答这些问题将产生关键的 关于PKC介导的信号转导功能的信息 细胞生长和分化的途径，以及 改变了这些途径在细胞转化中的调节。 信号转导机制的研究将有应用 在癌症诊断中，在设计治疗策略中， 在鉴定生长控制的分子机制方面， 在其他疾病过程中发挥作用。

Analysis of the mechanisms of cellular transformation by transduction of specific genes (by retroviral infection, by transfection of tumor cell DNA or by over-expression of normal cellular genes) indicate that a common feature is the alteration in the function or regulation of specific components in signal transduction pathways that mediate the response of cells to mitogenic stimulation. The long-term objectives of this application are to determine the molecular mechanisms involved in transformation induced by altered regulation of growth factor- mediated signal transduction pathways. A central factor in the mitogenic response involves the activation of protein kinase C (PKC), a calcium and phospholipid-dependent kinase that has been demonstrated to be activated in pathways of both proliferation and differentiation. Therefore, alterations in the regulation of PKC activity may have a dramatic effect on growth control. In fact, the over-expression of PKC activity and a PKC-regulated gene, termed phorbin, in fibroblasts has been demonstrated to induce a transformed phenotype. The preliminary evidence suggests that the mechanism of transformation by phorbin is mediated through an autocrine process. This application outlines an experimental approach to determine if alterations in PKC or phorbin gene expression can be identified in specific types of human tumors or transformed lines, to determine the role of the phorbin protein in transformation, to identify the critical regions of the protein that are required for the induction of transformation, and to determine the role of this protein in PKC-mediated effects on cell differentiation. Answering these questions will yield critical information about the function of PKC-mediated signal transduction pathways in cell growth and differentiation and about the role of altered regulation of these pathways in cellular transformation. Mechanistic studies of signal transduction will have applications in cancer diagnosis, in the design therapeutic strategies, and also in identification of the molecular mechanisms of growth control which that play a role in other disease processes.