This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Most chemotherapeutic approaches aim to kill cancer cells, usually by inducing apoptosis. Less well explored has been the possibility that cancer cells could be forced to stop proliferating, via induction of cellular senescence, without necessarily killing the cells as a direct result of the chemical treatment. It is hoped that such a strategy would produce milder side effects and therefore be better tolerated by patients. This project seeks to discover new regulatory systems that mediate senescence-like pathways to arrest cell growth. The human tumor suppressor p53 plays a vital role in the regulation of senescence. However, p53 also coordinates other cellular responses, such as apoptosis and DNA repair, and it is not known how these various responses are differentially effected by a common regulatory protein. We hypothesize that different modifications of p53 enable it to evoke cellular senescence under some circumstances and apoptosis, for example, under others. We plan to treat normal and cancerous human cells with various agents that induce senescence or other p53-mediated responses, and then analyze the molecular features of the various responses. After treatments, we will determine which post-translational modifications of p53 are produced and which p53-dependent transcriptional responses become activated. By connecting specific growth-arresting treatments to the distinct molecular features that direct changes in cellular physiology, we expect to identify regulatory targets and molecular hallmarks of the senescence pathway that will aid development of a novel class of antica
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