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The Contribution of p53 in the Dynamics of Cell Cycle Response to DNA Damage Interpreted by a Mathematical Model
Monica Lupi, Giada Matera, Claudia Natoli, Valentina Colombo and Paolo Ubezio
volume 6 | issue 8
15 April 2007Pages: 943 - 950
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Despite numerous studies on the tumor suppressor p53, a complete picture of its role in cell arrest and killing in G1, S and G2M 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 treatments 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 G1, S and G2M. 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 G1 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 G2M 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.
Authors
Monica Lupi
Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
Giada Matera
Istituto di Ricerche Farmacologiche
Claudia Natoli
Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
Valentina Colombo
Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
Paolo Ubezio
Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.