Deciphering p53 Programs in Lung Cancer Suppression

Cancer is caused when important genes involved in regulating cell division are mutated or altered. Alterations in genes known as “tumor suppressor genes”, which normally act like brakes to cell division, are commonly implicated in cancer.  One such tumor suppressor gene, p53, is frequently inactivated in lung cancers (~50% of cases), reflecting the fact that it normally imposes a critical brake on lung cancer development. p53 is known to act by promoting the production of other proteins in the cell, although those proteins most essential for mediating p53's effects in tumor suppression have remained enigmatic. In this proposal, we will use mouse lung cancer models to understand how p53 works as a lung cancer suppressor, with the goal of using that information to better devise therapies that might help inhibit lung cancer growth. Using novel and innovative genetic screening approaches, we previously identified proteins that p53 works through to suppress cancer in a cell model system, suggesting these are crucial proteins for suppressing cancer. Here, we propose to analyze these potential critical tumor suppressors in lung cancer mouse models, to comprehensively define the proteins through which p53 suppresses lung cancer in an organism. Upon identifying any key tumor suppressors in the mouse lung models, we will examine the importance of these genes in human lung cancer development.  Identifying essential players for mediating p53 function in suppressing lung cancer development is fundamental for designing better therapeutic approaches for treating human lung cancer.