The p53 tumor suppressor gene is the most commonly mutated gene in human cancer, highlighting its role as a critical barrier to tumor development. Moreover, p53 inactivation promotes cancer in nearly every mouse model analyzed. Despite this fundamental role in cancer suppression, however, the cellular and molecular underpinnings of p53-mediated cancer suppression remain enigmatic. p53 encodes a transcription factor that becomes activated in response to various stress signals, and induces diverse transcriptional networks to regulate numerous cellular processes, including proliferation, survival, metabolism, self-renewal, and motility. Thus, loss of p53 function triggers dramatic alterations in a cell that promote carcinogenesis. Interestingly, the mutations in p53 that arise in cancer are typically missense mutations, which not only inactivate p53 transcriptional activation function but also confer novel gain-of-function properties on p53 that further enhance tumor development. Understanding how loss of normal p53 function and gain of new properties promote cancer is key to developing better therapeutics for the many cancers in which p53 is mutated.

            In its capacity as a cellular stress sensor, p53 also plays physiological roles beyond tumor suppression as well as driving pathological responses in certain settings. For example, p53 plays beneficial roles such as promoting fertility and tanning, but can also provoke deleterious effects in certain situations, such as the side effects of cancer therapies or the phenotypes associated with specific developmental diseases. Thus, understanding p53 pathways in these contexts also has therapeutic utility.

            The overarching goal of our research is to better define the mechanisms by which the p53 protein acts in different settings, ranging from tumor suppression to responses to chemotherapeutics, to ultimately gain 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 understand how p53 acts mechanistically. We leverage technological innovation at Stanford in a variety of areas, including genomics, organoid-based cancer models, and high-throughput genetic screens, to acquire new insight into p53. Using these combined approaches, we intend to decipher the transcriptional networks that mediate p53 functions in different contexts, knowledge that will help us understand how to best promote the beneficial and minimize the detrimental effects of p53 in the clinic.     

Specific areas of investigation include:

·       Defining the transcriptional networks responsible for tumor suppression, using CRISPR/Cas9 and shRNA high-throughput genetic screening approaches

·       Illuminating the diverse cellular processes that p53 regulates as a tumor suppressor and the genes involved in those processes using CRISPR/Cas9 high-throughput screens

·       Identifying p53-interacting partners and post-translational modifications using mass spectrometry 

·       Elucidating the genes activated and repressed by p53 in diverse settings using ATAC-sequencing, ChIP-sequencing and RNA-sequencing

·       Identifying p53 inhibitors to develop 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

·       Understanding the interplay between p53 family members (p53, p63, and p73) in both development and cancer