The Contribution of p53 in the Dynamics of Cell Cycle Response to DNA Damage Interpreted by a Mathematical Model

Abstract

AbbreViAtioNs AbstrACtDespite 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 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 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.

Quantitative Assessment of the Complex Dynamics of G1, S, and G2-M Checkpoint Activities

“…Each cell line may use the same bricks to build up the drug response with different strength, or not use one brick at all if the line is defective for important proteins of the associated network. Similar studies with other cell lines have qualitatively confirmed the responses with IGROV1 (5) and revealed the contribution of particular molecular defects in each checkpoint activity (4).…”

“…We applied our modeling approach on the measures taken with different techniques after treatments with five "classic" anticancer drugs, at concentrations spanning the whole range of drug efficacy, and at several times after drug exposure. Specific comments to cell cycle effects of each drug and possible connections to molecular mechanisms of action were discussed in other publications (1)(2)(3)(4)(5). Exploiting the fact that the cell line, the experimental plan, and techniques were the same, we were able to create a database including data on all the drugs together, and we analyzed the results synoptically to extract the general features of the dynamics of G 1 , S, and G 2 -M checkpoint activities.…”

Reverse engineering of drug induced DNA damage response signalling pathway reveals dual outcomes of ATM kinase inhibition

“…In the past, several researchers have targeted a variety of dynamical processes within biological systems for their computational analysis ranging from studies into parallel reaction pathways [130], HBV infections [131] and in silico analysis of SarCoV [132]. In terms of DDR signalling pathway, most of systems biology studies have been undertaken to examine and model the oscillatory patterns of DDR protein induction following DNA damage in light of the known biological insights [133][134][135]137] with some reports focussing on elucidating the role of such oscillations in determining cell fate i.e. DNA repair, cell cycle arrest or apoptosis [88,100,103,138].…”

Application of primary cell cultures of laryngeal carcinoma and laser scanning cytometry in the evaluation of tumor reactivity to cisplatinum.

“…Recent studies have demonstrated that at least two pathways regulate apoptosis: one dependent on the tumor suppressor gene P53 and the other P53-independent [11,12].…”