A05: Dissecting the basis of the cell death decisions mediated by p53 mutants

Project Leaders: Ivano Amelio, Andreas Gruber

In response to damaging stressors the transcription factor p53 contributes to determining the decisions between life and death. In human cancers, the frequently observed missense mutations of p53 produce a major disruption of apoptotic death decision processes due to loss of the p53 wild type function, but also with the acquisition of gain-of-function (GOF) mutant proteins, with novel functions exerting influence on the mechanisms of cellular death decision-making. p53 mutant GOF effects emerge to a high degree in context-dependency. We demonstrated that p53 mutant proteins acquire selective pro-tumorigenic properties under hypoxia and we observed that p53 mutant expression differentially influences cell fate in vitro and in vivo. Based on substantial preliminary data, this project addresses the highly relevant feature that p53 GOF mutants represent crucial factors in life/death decisions, with their function manifesting in specific microenvironmental contexture. With a complementary experimental molecular biology and computational systems biology research plan, we will dissect the basis of the cell death decisions mediated by p53 mutants and based on preliminary evidence we hypothesize that mitochondrial fitness represents the functional hub of the context-dependent effects mediated by p53 mutants. In the first part, we plan to determine p53 mutant-dependent effects on life/death decisions comparing different models (in vitro 2D, 3D, in vivo) and altered environmental conditions (oxygen and/or nutrient deprivation). In the second part, we will employ computational modelling to reconstruct the underlying gene regulatory network and we will validate the predictions in our experimental models. In the final part, we plan to dissect the influence of the mitochondrial fitness on the p53 mutant-mediated cell death process, generating causative relationships with the identified gene regulatory network. The results of our research will provide the molecular basis of life/death decisions in p53 mutant cells and will inform on potential strategies of intervention to direct cell fate.