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.
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