Mutations in the gene p53 occur in a wide range of human cancers and are often associated with aggressive tumor behavior and poor patient prognosis. Wild-type p53 is activated by DNA damage and various forms of oncogenic stress, inducing genes that promote cell-cycle blockade, apoptosis, senescence, differentiation and/or autophagy. In fact, activated p53 can suppress epigenetic reprogramming of differentiated cells into induced pluripotent stem cells. In addition to its cell-autonomous activities, p53 can promote the secretion of a variety of factors that influence the tissue microenvironment in a non–cell autonomous manner.
Which of these p53 activities is most relevant for the protein’s tumor suppressor role has been widely debated and is likely context-dependent.
Our lab has a long-standing interest in p53 stemming from our early observations that p53 could promote apoptosis in response to oncogenes and DNA-damaging cytotoxic drugs (1), (2). Indeed, we showed that p53 loss compromised the ability of certain cells to undergo therapy-induced apoptosis, thereby providing some of the first evidence that tumor-cell response to therapy could be dictated by cancer genotype and that p53 mutations could promote drug resistance. We also showed that p53 can be activated by oncogenes and have explored the molecular basis for this tumor-suppressive effect.
Over the last decade, we have focused on the roles and regulation of p53 in vivo. For example, we have shown that p53 loss is required for cancer maintenance (3), (4). We are currently exploring the role of specific p53 mutants on cancer metastasis and the processes by which p53 acts to limit cellular plasticity and liver carcinogenesis.