title: Positive effect of Mdm2 on p53 expression explains excitability of p53 in response to DNA damage.
abstract: Most of the existing biological models consider Mdm2 as a dominant negative regulator of p53 appearing in several negative feedback loops. However, in addition to targeting p53 for degradation, Mdm2 in tight cooperation with MdmX can control expression levels of p53 through enhanced induction of p53 synthesis in response to DNA damage. Whilst ATM-dependent phosphorylation of p53 is not observed to be important in this enhanced synthesis, ATM-dependent phosphorylation of Mdm2 (as well as MdmX) is essential for its dual role, which is accompanied with widely oscillating p53. In the light of these new observations we formulate a novel molecular mechanism which, in silico, is capable of triggering p53 oscillations. The mechanism that is based on Mdm2's dual regulation of p53 can provide mechanistic insights into an excitability of the p53 network, thus it contributes to understanding of variability of p53 dynamics in response to single and double strand breaks.
authors.affiliation: Laboratoire de Mathématiques d'Orsay, Univ. Paris-Sud, CNRS, Université Paris-Saclay, 91405 Orsay, France; Sorbonne Universités, Inria, UPMC Univ Paris 06, Lab. J.L. Lions UMR CNRS 7598, Paris, France. Electronic address: jan.elias@inria.fr.
authors.forename: Ján
authors.initials: J
authors.lastname: Eliaš
mesh_terms: D000818:Animals; D001683:Biological Clocks; D018797:Cell Cycle Proteins; D003198:Computer Simulation; D053903:DNA Breaks, Double-Stranded; D053904:DNA Breaks, Single-Stranded; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Excitability; Mdm2; Oscillations; P53; Reaction-diffusion model