ENVIRONMENTAL STRESS AGENTS AND SIGNAL TRANSDUCTION

描述：许多环境毒素诱导一种类固醇应激反应 包括c-fos的诱导和蛋白质的暂时抑制 合成. 识别由细胞因子诱导的常见细胞信号传导机制 不同类型的压力源对于理解细胞如何 反应促进细胞在面对细胞毒性损伤时的存活。 的 申请人已经证明， 在暴露于应激物后， 翻译起始因子eIF-2a，增加MAP激酶活性， 激活ELK-1转录因子。 他假设， 应激诱导的eIF-2a磷酸化是一种常见的信号转导途径， 钙应激源、氧化应激源和紫外线 辐射 此外，他提出了一个模型，其中eIF-2a诱导 翻译停滞导致MAP激酶的丰度降低 磷酸酶，这反过来又增加MAP激酶的活性，并激活 ELK-1和c-fos转录。 该提案有两个具体目标：1） 确定翻译停滞是否作为一种常见机制 介导环境应激对c-fos表达的诱导; 2)为了确定c-Fos蛋白在促进 细胞存活和对环境压力的耐受性。 第一 特异性靶向使用用“显性阴性”形式的 阻断内源性eIF-2a的磷酸化并防止 翻译停滞 申请人将测试 eIF-2a的突变形式将阻断MAP激酶和ELK-1的活化， 通过各种类型的应激物对c-fos的转录激活。 在 第二个具体目标，来自c-fos敲除小鼠的胚胎成纤维细胞 目的研究c-Fos蛋白在促进细胞凋亡中的作用。 生存和获得耐受性。

DESCRIPTION: Many environmental toxins induce a sterotypic stress response which includes the induction of c-fos and a temporary suppression of protein synthesis. Identifying the common cellular signaling mechanism induced by different types of stressors is important to understanding how cellular responses promote cell survival in the face of cytotoxic damage. The applicant has demonstrated that the inhibition of protein synthesis seen after exposure to stressors is associated with phosphorylation of the translation initiation factor eIF-2a, increased MAP kinases activities, and activation of the ELK-1 transcription factor. He hypothesizes that stress-induced phosphorylation of eIF-2a represents a common signaling mechanism used by calcium stressors, oxidative stressors and ultraviolet radiation. Furthermore, he proposes a model in which eIF-2a-induced translational arrest results in a decrease in the abundance of MAP kinase phosphatase which, in turn, increases MAP kinases activities and activates ELK-1 and c-fos transcription. The proposal has two specific aims: 1) to determine whether translational arrest serves as a common mechanism mediating the induction of c-fos expression by environmental stressor; and 2) to determine the physiological significance of c-Fos protein in promoting cellular survival and tolerance to environmental stressors. The first specific aim employs cells transfected with a "dominant-negative" form of the eIF-2a that blocks the phosphorylation of endogenous eIF-2a and prevents translational arrest. The applicant will test whether expression of the mutant form of eIF-2a will block MAP kinase and ELK-1 activation and the transcriptional activation of c-fos by various classes of stressors. In the second specific aim, embryo fibroblasts derived from c-fos knockout mice will be used to investigate the role of c-Fos protein in promoting cell survival and acquisition of tolerance in response to environmental stressor.