title: MiR-192-Mediated Positive Feedback Loop Controls the Robustness of Stress-Induced p53 Oscillations in Breast Cancer Cells.
abstract: The p53 tumor suppressor protein plays a critical role in cellular stress and cancer prevention. A number of post-transcriptional regulators, termed microRNAs, are closely connected with the p53-mediated cellular networks. While the molecular interactions among p53 and microRNAs have emerged, a systems-level understanding of the regulatory mechanism and the role of microRNAs-forming feedback loops with the p53 core remains elusive. Here we have identified from literature that there exist three classes of microRNA-mediated feedback loops revolving around p53, all with the nature of positive feedback coincidentally. To explore the relationship between the cellular performance of p53 with the microRNA feedback pathways, we developed a mathematical model of the core p53-MDM2 module coupled with three microRNA-mediated positive feedback loops involving miR-192, miR-34a, and miR-29a. Simulations and bifurcation analysis in relationship to extrinsic noise reproduce the oscillatory behavior of p53 under DNA damage in single cells, and notably show that specific microRNA abrogation can disrupt the wild-type cellular phenotype when the ubiquitous cell-to-cell variability is taken into account. To assess these in silico results we conducted microRNA-perturbation experiments in MCF7 breast cancer cells. Time-lapse microscopy of cell-population behavior in response to DNA double-strand breaks, together with image classification of single-cell phenotypes across a population, confirmed that the cellular p53 oscillations are compromised after miR-192 perturbations, matching well with the model predictions. Our study via modeling in combination with quantitative experiments provides new evidence on the role of microRNA-mediated positive feedback loops in conferring robustness to the system performance of stress-induced response of p53.
authors.affiliation: Bioengineering Department, University of Texas at Dallas, Richardson, Texas, United States of America.|Center for Systems Biology, University of Texas at Dallas, Richardson, Texas, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Moore
authors.affiliation: Bioengineering Department, University of Texas at Dallas, Richardson, Texas, United States of America.
authors.forename: Hsu Kiang
authors.initials: HK
authors.lastname: Ooi
authors.affiliation: Bioengineering Department, University of Texas at Dallas, Richardson, Texas, United States of America.|Center for Systems Biology, University of Texas at Dallas, Richardson, Texas, United States of America.
authors.forename: Taek
authors.initials: T
authors.lastname: Kang
authors.affiliation: Bioengineering Department, University of Texas at Dallas, Richardson, Texas, United States of America.|Center for Systems Biology, University of Texas at Dallas, Richardson, Texas, United States of America.|Electrical Engineering Department, University of Texas at Dallas, Richardson, Texas, United States of America.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Bleris
authors.affiliation: Bioengineering Department, University of Texas at Dallas, Richardson, Texas, United States of America.
authors.forename: Lan
authors.initials: L
authors.lastname: Ma
mesh_terms: D001683:Biological Clocks; D001943:Breast Neoplasms / Q000503:physiopathology*; D003198:Computer Simulation; D004249:DNA Damage; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C546783:MIRN192 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53