Illuminating the P53 Regulatory Network in Genetic Models
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The tumor suppressor gene p53 is mutated in more than 50% of human cancers, and functions as a central component of stress response machinery that mediates a wide variety of downstream responses. Interestingly, the evolutionary appearance of p53 preceded its role in tumor suppression, suggesting that there may be unappreciated functions for this protein. In order to examine physiologic functions of p53 in vivo, a green fluorescent protein (GFP) reporter was designed to follow the activation of this regulatory network in a genetic model, Drosophila melanogaster. By following the reporter during Drosophila development, physiological activation of the p53 regulatory network in the female germ line was discovered. It is provoked by the first enzymatic step for meiotic recombination and conserved in both flies and mice. The functional relevance of the p53 activities in the germ line was shown by the meiotic recombination frequency and genetic interactions with a meiotic effector gene, Rad54. Additionally, genotoxic stress selectively activates p53 in germ line stem cells and promotes regeneration of fertility after IR. Activation of p53 was also found in uncontrolled growth of germ cells by blocked differentiation, and surprisingly by overexpression of oncogenic protein in the germ line. Together, my thesis work indicate that the need for controlling growth by the p53 regulatory network is an evolutionary conserved feature, which may serve as a selective pressure to preserve this network. Future studies on the mechanisms of p53 actvities during meiosis and in response to oncogene activation could provide novel insights on its cancer-related functions.