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The p53 Regulatory Network in Drosophila

The p53 tumor suppressor gene is mutated in most human cancers and is perhaps the most highly studied in all of biomedical research.  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 an incredibly rich body of knowledge about the function of p53.  However, very 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 at the tissue level, we initiated a comprehensive analysis of the sole p53 family member encoded in the Drosophila genome, Dp53.  Like its counterpart in mammalian systems, Dp53 is a crucial determinant of genome stability and is also essential for stress-induced apoptotic responses.  We further demonstrated that the pro-apoptotic activator, reaper, is an authentic Dp53 target in vivo.  Hence, in this model,the Dp53/rpr 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.  Because surrounding tissue fundamentally influences cell behavior, a strength of our approach comes from directed exploration of molecular circuits within a whole animal model.  Current projects follow stimulus-dependent p53 action in live tissues to discover new determinants that specify adaptive responses beyond the single cell level.