STRESS RESPONSES AND APOPTOSIS

描述：(改编自调查人员摘要) 这项提议的总体目标是检验这样一种假设 细胞对凋亡诱导的敏感性受以下因素调节 内源性应激反应对扰动或 细胞器功能。眼下的焦点是压力反应。 由thapsigarin介导的内质网耗竭触发 网状(ER)钙池。这种压力反应包括 三种内质网钙结合蛋白的转录诱导： GRP78、GRP94和钙网织蛋白。信号机制，要么调解 或抑制内质网应激反应及内质网应激反应的作用 在确定细胞对凋亡的敏感性方面， 调查过了。这项提案中计划进行的实验的理由是 基于有证据表明内质网应激反应不足是导致 WEH17.2小鼠淋巴瘤细胞对凋亡的异常敏感性，以及 该细胞系的内质网应激反应缺陷是由于 蛋白酶体介导的c-Fos降解。该提案有四个具体内容 目的：(1)研究c-Fos和c-Jun在调节和/或 抑制内质网应激反应；(2)体细胞杂交 WEH17.2细胞内质网应激反应缺陷的机制研究 细胞；(3)使用功能选择策略来识别cDNA 编码介导或抑制内质网应激反应的蛋白质；(4) 研究内质网应激反应在细胞调控中的作用 对诱导细胞凋亡的敏感性。通过这种方式获得的知识 建议将作为研究内源的作用的基础。 细胞应激反应在确定不同细胞因子敏感性中的作用 从癌症类型到诱导细胞凋亡的化疗药物。此外， 介导内源性应激反应的信号通路，一旦 已确定的，将成为旨在 废除细胞保护机制，从而减少生长和 肿瘤细胞的转移潜能，并增加对肿瘤的敏感性 化疗诱导肿瘤细胞凋亡。

DESCRIPTION: (adapted from the investigators abstract) The overall goal of this proposal is to test the hypothesis that the susceptibility of cells to apoptosis induction is regulated by endogenous stress responses induced in response to perturbation or organelle function. The immediate focus is on the stress response triggered by thapsigargin-mediated depletion of the endoplasmic reticulum (ER) calcium pool. This stress response includes transcriptional induction of three resident ER calcium-binding proteins: Grp78, Grp94 and calreticulin. Signaling mechanisms that either mediate or repress the ER stress response and the role of the ER stress response in determining the susceptibility of cells to apoptosis will be investigated. The rationale for experiments planned in this proposal is based on evidence that a deficient ER stress response accounts for the unusual susceptibility of WEH17.2 mouse lymphoma cells to apoptosis, and that the deficient ER stress response in this cell line is due to proteasome-mediated degradation of c-Fos. The proposal has four specific aims: (1) Investigate the roles of c-Fos and c-Jun in mediating and/or repressing the ER stress response; (2) Use somatic cell hybridization to investigate the mechanism of ER stress response deficiency in WEH17.2 cells; (3) Use a functional selection strategy to identify cDNAs encoding proteins that mediate or repress the ER stress response; (4) Investigate the role of the ER stress response in regulating cellular susceptibility to apoptosis induction. Knowledge gained through this proposal will serve as a basis for investigating the role of endogenous cellular stress responses in determining the sensitivity of different types of cancer to apoptosis-inducing chemotherapeutic agents. Moreover, signaling pathways that mediate endogenous stress responses, once identified, will be potential targets of novel therapeutics designed to abrogate cellular protective mechanisms, thereby reducing the growth and metastatic potential of tumor cells, and increasing the sensitivity of tumor cells to chemotherapy-induced apoptosis.