PROTECTION AGAINST APOPTOSIS BY SCATTER FACTOR

描述：散射因子(SF)或肝细胞生长因子(HGF)是一种 参与多种生物学过程的细胞因子，包括 癌变、上皮形态发生和器官修复。申请人 已经发现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导致细胞数量增加 生死存亡。保护依赖于c-Met的表达 原癌基因，SF的受体，但不需要功能性的P53。 对阿霉素的保护作用可能是由于血药浓度的变化 不同的细胞凋亡调控蛋白。调查人员的假设是 SF介导的靶细胞保护是通过转导 来自激活的c-Met的特定信号，不同于 运动性和形态发生。这一信号导致了下游的变化 细胞凋亡调节蛋白的水平。通过提高人类的生存能力 有遗传损伤的细胞，SF可能促进致癌和/或 已建立的肿瘤的化疗-放射耐药。申请者提议测试 这些假设在特定的目标1和2中通过检验机制 哪种SF保护上皮和癌细胞免受细胞凋亡的影响 C-Met受体的信号转导水平及其调控 参与细胞凋亡、细胞周期进程和DNA修复的通路。在……里面 具体目标3，将使用一个实验动物模型来确定SF 可以保护肿瘤免受细胞凋亡的影响。

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.