title: A spatial physiological model for p53 intracellular dynamics.
abstract: In this paper we design and analyse a physiologically based model representing the accumulation of protein p53 in the nucleus after triggering of ATM by DNA damage. The p53 protein is known to have a central role in the response of the cell to cytotoxic or radiotoxic insults resulting in DNA damage. A reasonable requirement for a model describing intracellular signalling pathways is taking into account the basic feature of eukaryotic cells: the distinction between nucleus and cytoplasm. Our aim is to show, on a simple reaction network describing p53 dynamics, how this basic distinction provides a framework which is able to yield expected oscillatory dynamics without introducing either positive feedbacks or delays in the reactions. Furthermore we prove that oscillations appear only if some spatial constraints are respected, e.g. if the diffusion coefficients correspond to known biological values. Finally we analyse how the spatial features of a cell influence the dynamic response of the p53 network to DNA damage, pointing out that the protein oscillatory dynamics is indeed a response that is robust towards changes with respect to cellular environments. Even if we change the cell shape or its volume or better its ribosomal distribution, we observe that DNA damage yields sustained oscillations of p53.
authors.affiliation: INRIA Paris-Rocquencourt & UPMC, 4 Place Jussieu, F-75005 Paris, France. luna.dimitrio@inria.fr
authors.forename: Luna
authors.initials: L
authors.lastname: Dimitrio
authors.forename: Jean
authors.initials: J
authors.lastname: Clairambault
authors.forename: Roberto
authors.initials: R
authors.lastname: Natalini
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D064007:Ataxia Telangiectasia Mutated Proteins; D001683:Biological Clocks / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D004058:Diffusion; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D008954:Models, Biological; D008962:Models, Theoretical; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D014018:Tissue Distribution / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases