The p53 protein and its molecular network: modelling a missing link between DNA damage and cell fate

Abstract : Various molecular pharmacokinetic-pharmacodynamic (PK-PD) models have been proposed in the last decades to represent and predict drug effects in anticancer chemotherapies. Most of these models are cell population based since clearly measurable e ects of drugs can be seen, much more easily than in individual cells, on populations of cells, healthy and tumour. The actual targets of drugs are, however, cells themselves. The drugs in use either disrupt genome integrity by causing DNA strand breaks, and consequently initiate programmed cell death, or block cell proliferation mainly by inhibiting factors that enable cells to proceed from one cell cycle phase to the next through checkpoints in the cell division cycle. DNA damage caused by cytotoxic drugs (and also cytostatic drugs at high concentrations) activates, among others, the p53 protein-modulated signalling pathways that directly or indirectly force the cell to make a decision between survival and death. The paper aims to become the first-step in a larger scale enterprise that should bridge the gap between intracellular and population PK-PD models, providing oncologists with a rationale to predict and optimise the effects of anticancer drugs in the clinic. So far, it only sticks at describing p53 activation and regulation in single cells following their exposure to DNA damaging stress agents. We show that p53 oscillations that have been observed in individual cells can be reconstructed and predicted by compartmentalising cellular events occurring after DNA damage, either in the nucleus or in the cytoplasm, and by describing network interactions, using ordinary di erential equations (ODEs), between the ATM, p53, Mdm2 and Wip1 proteins, in each compartment, nucleus or cytoplasm, and between the two compartments.
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BBA - Proteins and Proteomics, Elsevier, 2013, <10.1016/j.bbapap.2013.09.019>
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Jan Elias, Luna Dimitrio, Jean Clairambault, Roberto Natalini. The p53 protein and its molecular network: modelling a missing link between DNA damage and cell fate. BBA - Proteins and Proteomics, Elsevier, 2013, <10.1016/j.bbapap.2013.09.019>. <hal-00822308v2>

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