Cellular Stress Response Signaling Pathways

Kastan, Michael

Abstract

Elucidation of the specific steps involved in signal transduction pathways activated in cellular responses to DNA damage and other cellular stresses can provide critical insights into the genesis of malignancies and suggest new therapeutic approaches. Inhibitors of topoisomerase I have become an important component of our armamentarium in treating human cancers, however, little is known about the signal transduction pathways that participate in cellular responses to these agents. Experiments are proposed here that will elucidate the signaling pathways that are activated in cells following exposure to topoisomerase I inhibitors, including the roles of ATM and/or ATR and the numerous proteins that have been found to be downstream of these protein kinases in other cellular responses. Hypoxia is a cellular stress that plays a critical role in tumor development and appears to influence tumor prognosis. Studies are proposed that will also elucidate the cellular signaling pathways that determine cellular outcome in the presence of hypoxic stress. Since many of the steps in these pathways participate in controlling specific stages of the cell cycle, these characterizations should provide new insights into the nature of the cellular lesions that are present following exposure to these cellular stresses. P53 protein is one of the critical modulators of cellular responses to stress and a series of proposed experiments specifically address the regulation of p53 protein levels and function following DNA damage and hypoxia. In particular, continued or enhanced translation of p53 protein in the face of these stresses suggests a unique mechanism of translational regulation and the role of the 5'-UTR of p53 in this process will be investigated. In addition, experiments are proposed that will elucidate the importance of post-translational modifications of p53 protein and cellular redox status in controlling the ability of p53 protein to bind to specific DNA promoter sequences following stress. Finally, one of the major goals of understanding the molecular basis of these responses is to improve interventions in the treatment of cancer. Towards this end, responses of tumor xenografts with specific lesions in one or more of the signaling steps in these pathways will be examined. In tow, these studies should provide significant new information that has implications for both tumor development and therapy.