Oncogenic Functions of Mutant p53

Abstract The tumor suppressor gene, p53, has pleiotropic functions that quash tumor development. One of its most important functions is to prevent the genome from sustaining DNA damage in order to prevent the propagation of genetic lesions into daughter cells. Given the high degree of genetic alterations in cancer, it is not surprising that p53 is frequently inactivated. The most common form of genetic lesions in the p53 gene are point mutations in the DNA binding domain. These missense mutations typically inactivate the p53’s tumor suppressor activity while simultaneously generating an oncogenic protein. The presence of mutant p53 correlates with increased chromosomal instability leading to loss of tumor suppressor genes and amplification of oncogenes. It has become increasingly recognized that the cGAS/STING/TBK1/IRF3 innate immune response signaling pathway plays a crucial role in detecting genetic alterations and launching cell intrinsic and extrinsic responses to suppress aberrant cells that harbor genetic defects. In this proposal, we that mutant p53 suppresses signaling through the cGAS/STING pathway and thereby dictates how cells respond to its activation. We propose three aims to determine the mechanism by which mutant p53 controls cGAS/STING signaling, and the cell intrinsic and extrinsic consequences of modulation of this pathway. The completion of these studies will help guide how to therapeutically approach cancers based on their p53 status.