p53 genes are widely implicated in age-related diseases. The p53 tumor suppressor gene is mutated in most human cancers. The gene acts to preserve genome stability and constrain oncogenic potential by governing adaptive responses to genotoxic stress.
At the single-cell level, we have a rich body of knowledge about the function of p53. However, little is known about how this gene functions among cell groups to elicit adaptive responses at the tissue level. To illuminate core ancestral functions of this critical tumor suppressor and understand how this gene coordinates injury responses in tissue, we initiated a comprehensive analysis of Dp53, the Drosophila homolog of p53. Like its mammalian counterpart, Dp53 is crucial for genome stability and also for stress-induced apoptotic responses. We further demonstrated that the pro-apoptotic activator, reaper, is an authentic Dp53 target in vivo.
The Dp53/reaper axis contributes important functions during unscheduled apoptosis as an adaptive response to injury. Our research continues to explore conserved properties of adaptive stress responses as they engage the p53 regulatory network.
Using the Drosophila model, we identified a signature profile for p53-dependent stress responses and established a novel method to examine the pro-apoptotic action of p53 in living animals. Together with real-time imaging methods, these tools permit us to examine p53-driven behaviors of living cells in situ.
We are following stimulus-dependent p53 action in live tissues to discover new determinants that specify adaptive responses beyond the single-cell level. From these studies, we found that p53 acts selectively in stem cells.
More recently, we discovered that mutations in p53 genes permit eruptions of mobile elements, known as transposons. We are exploring how p53 contains mobile elements and interrogating pathologic outcomes triggered by unrestrained transposons. At the same time, we are also testing interventions that could mitigate p53-driven ’transposopathies’ by inhibiting the action of these mobile elements.