The contribution of p53 in the dynamics of cell cycle response to DNA damage interpreted by a mathematical model

Despite numerous studies on the tumor suppressor p53, a complete picture of its role in cell arrest and killing in G(1), S and G(2)M phases after drug treatment is lacking. We tackled the analysis of the complexity of cell cycle effects combining the time - course measures with different techniques with the aid of a computer program simulating cell cycle progression. This mixed experimental - simulation approach enabled us to decode the dynamics of the cytostatic and cytotoxic responses to cisplatin and doxorubicin treat ments in a p53 - proficient colon carcinoma cell line ( HCT - 116) and in its p53 - deficient counterpart. We achieved a separate evaluation of the activity of each cell cycle control and we connected these results with measures of p53 level in G(1), S and G(2)M. We confirmed the action of p53 in all cell cycle phases, but also the presence of strong p53 - independent cytostatic and cytotoxic activities exerted by both drugs. In G(1) phase, p53 was responsible for a medium/ long term block, distinct from the short - term block, which was p53 - independent. The delay in traversing S phase was reduced by the presence of p53. In G(2)M phase, despite a strong p53 - independent block, there was a weaker but more persistent p53 - dependent block. At cytotoxic concentrations, p53 - dependent and p53 - independent cell death was observed. The former was poorly phase - specific, occurred earlier and exploited the apoptotic mechanism more than p53 - independent death. Computer simulation produced a framework where previous partial and sometimes apparently contradictory observations of the p53 - mediated effects could be reconciled and explained.