STRESS RESPONSES AND APOPTOSIS

描述：（改编自研究者摘要） 本提案的总体目标是检验以下假设： 细胞对凋亡诱导的敏感性由 对扰动的反应引起的内源性应激反应， 细胞器功能当前的焦点是压力反应 由毒胡萝卜素介导的内质网耗竭引发 内质网钙池。这种应激反应包括 三种常驻ER钙结合蛋白的转录诱导： Grp 78、Grp 94和钙网蛋白。信号传导机制， 或抑制内质网应激反应以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， 研究了本提案中计划进行的实验的基本原理是 基于证据表明，ER应激反应不足导致了 WEH 17.2小鼠淋巴瘤细胞对凋亡的异常易感性，以及 这种细胞系中缺乏内质网应激反应是由于 蛋白酶体介导的c-Fos降解。该提案有四个具体的 目的：（1）调查c-Fos和c-Jun在调解和/或 抑制ER应激反应;（2）利用体细胞杂交 探讨WEH17.2细胞内质网应激反应缺陷的机制 （3）使用功能性选择策略鉴定cDNA 编码介导或抑制ER应激反应的蛋白质;（4） 研究内质网应激反应在调节细胞凋亡中的作用， 对凋亡诱导的易感性。通过这个获得的知识 建议将作为调查内源性作用的基础， 细胞应激反应在确定不同的敏感性 类型的癌症对诱导化疗剂的耐受性。此外，委员会认为， 信号通路介导内源性应激反应，一旦 将成为新疗法的潜在靶点， 消除细胞保护机制，从而减少生长， 肿瘤细胞的转移潜力，并增加敏感性 肿瘤细胞对化疗诱导的凋亡的影响。

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.