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The observations that the p53 gene is mutated in at least half of all human cancers of a wide variety of types and that p53 null mice develop cancer at 100% frequency together underscore the critical role for p53 in tumor suppression. Wild-type p53 is a cellular stress sensor, responding to diverse insults such as DNA damage, hyperproliferative signals, and hypoxia by inducing growth arrest or apoptosis, responses thought to be important to tumor suppression. At the molecular level, p53 acts a transcription factor that activates gene expression programs to induce these different responses. Interestingly, in its capacity as a cellular stress sensor, p53 also plays physiological roles beyond tumor suppression as well as causing certain pathological effects. For example, p53 plays beneficial roles such as promoting fertility, and can promote detrimental phenotypes in certain situations such as the side effects of cancer therapies or developmental diseases. The overarching goal of our research is to better define the mechanisms by which the p53 protein promotes different responses in different settings, ranging from tumor suppression to responses to chemotherapeutics, using the mouse as an in vivo model system, with the ultimate goal of gaining insight that may facilitate clinical advances in diagnosis, prognostication and therapy. We utilize a combination of mouse genetic, cell biological, biochemical, and genomic approaches to address understand how p53 acts mechanistically. We hope to decipher the transcriptional networks responsible for mediating p53 functions in different contexts, an understanding that will help us understand how to best promote the beneficial and minimize the detrimental effects of p53 in the clinic.We have a number of specific areas of investigation, which include:* Defining the transcriptional networks responsible for tumor suppression, using CRISPR/Cas9 and shRNA high-throughput genetic screening approaches* Identifying p53-interacting partners by mass spectrometry approaches* Elucidating the genes activated and repressed by p53 in diverse settings using genomic technologies such as ChIP-sequencing and RNA-sequencing, to understand how p53 drives different responses* Identifying p53 inhibitors to find strategies to suppress the detrimental effects of p53 activation, such as during cancer therapy* Understanding p53’s role in developmental diseases such as CHARGE syndrome* Characterizing p53-regulated noncoding RNAs and their roles in cancer* Examining mechanisms of p53 gain-of-function properties in cancer