PROTECTION AGAINST APOPTOSIS BY SCATTER FACTOR

描述：分散因子（SF）或肝细胞生长因子（HGF）是一种 参与多种生物过程的细胞因子，包括 癌发生、上皮形态发生和器官修复。 申请人 发现SF可以保护培养的乳腺癌细胞和非肿瘤细胞， 抗多种DNA损伤剂诱导的上皮细胞凋亡， 包括X射线、紫外线照射和阿霉素， 生存 保护作用依赖于c-Met的表达 原癌基因，SF的受体，但不需要功能性p53。 对阿霉素的保护作用可能是由于 不同的凋亡调节蛋白。 研究人员假设 SF介导的对靶细胞的保护作用是由 来自活化的c-Met的特异性信号不同于 运动和形态发生。 这个信号导致下游的改变， 凋亡调节蛋白的水平。 通过提高 具有遗传损伤的细胞，SF可能促进致癌作用和/或 已建立的肿瘤的化学放射抗性。 申请人建议测试 具体目标1和2中的这些假设， SF保护上皮细胞和癌细胞免于凋亡， 来自c-Met受体的信号转导水平和 参与细胞凋亡、细胞周期进程和DNA修复的途径。 在 具体目的3，将使用实验动物模型来确定SF是否 可以保护肿瘤细胞免于凋亡。

DESCRIPTION: Scatter factor (SF) or hepatocyte growth factor (HGF) is a cytokine implicated in diverse biological processes, including carcinogenesis, epithelial morphogenesis and organ repair. The applicant has found that SF can protect cultured breast cancer cells and non-tumor epithelial cells against apoptosis induced by multiple DNA damaging agents, including x-ray, UV irradiation and adriamycin leading to an increased cell survival. Protection was dependent on the expression of the c-Met proto-oncogene, the receptor for SF, but did not require functional p53. The protection seen against adriamycin may result from changes in the levels of different apoptosis regulatory proteins. The investigators hypothesize that SF mediated protection of target cells results from the transduction of a specific signal from the activated c-Met distinct from signals for motility and morphogenesis. This signal leads to downstream alterations in the levels of apoptosis regulatory proteins. By enhancing the survival of cells with genetic damage, SF may promote carcinogenesis and/or chemoradioresistance of established tumors. The applicant proposes to test these hypotheses in specific aims 1 and 2 by examining the mechanism by which SF protects epithelial and carcinoma cells against apoptosis at the levels of signal transduction from the c-Met receptor and modulation of pathways involved in apoptosis, cell cycle progression and DNA repair. In specific aim 3, an experimental animal model will be used to determine if SF can protect tumors against apoptosis.