The gene that encodes the p53 transcription factor is the most commonly mutated gene in human cancers, underscoring its fundamental role as a barrier to cancer development. However, while restoring p53 function in cancers represents an important anti-cancer strategy, inappropriate p53 activation in normal tissues can be toxic. Understanding how to achieve an appropriate balance of p53 activity is therefore critical for improved cancer therapeutics.

The overarching goal of the research in my laboratory has been to better understand the cellular mechanisms and transcriptional programs through which p53 drives different responses in different settings. We study how p53 promotes both beneficial effects, such as in cancer suppression, and deleterious effects in normal tissues, such as during embryonic development or in adult tissues exposed to DNA-damaging cancer therapeutics. Our work on p53 in tumor suppression has focused in particular on lung and pancreatic cancers, and we have shown that p53 tumor suppressor activity is mechanistically distinct from its ability to drive side effects in response to chemotherapies, suggesting the possibility of dampening the latter without compromising tumor suppression. Our work has suggested, further, that p53 relies on noncanonical cellular functions, such as restricting cellular plasticity and promoting differentiation, to suppress cancer, and we have characterized such tumor suppressive programs in detail. My laboratory has also uncovered a role for p53 in driving multi-symptom developmental syndromes, such as CHARGE Syndrome, and we have analyzed how different spatial and temporal profiles of p53 activation drive different constellations of phenotypes. Ultimately, elucidating the mechanisms underlying the beneficial and deleterious effects of p53 action is critical for devising the best strategies to target the p53 pathway in cancer and in pathological contexts.