A simple stochastic model for the feedback circuit between p16INK4a and p53 mediated by p38MAPK: implications for senescence and apoptosis.
The mechanisms leading to the cell fate decision between apoptosis and senescence upon DNA damage are still unclear and have stochastic features. Cellular oxidative stress can generate DNA damage and activate the important mitogen-activated protein kinase 14 (p38MAPK) that is involved in pathologies like Alzheimer's disease. Based on experimental evidence we propose a simple network that might operate at the core of the cell control machinery for the choice between apoptosis and senescence involving the cross-talk between p38MAPK, the tumor suppressor protein p53 and the cyclin-dependent kinase inhibitor (p16INK4a). We have performed two types of analyses, deterministic and stochastic, exploring the system's parameter space, in the first, we calculated the fixed points of the deterministic model and, in the second, we numerically integrated the master equation for the stochastic version. The model shows a variety of behaviors dependent on the parameters including states of high expression levels of p53 or p16INK4a that can be associated with an apoptotic or senescent phenotype, respectively, in agreement with experimental data. In addition, we observe both monostable and bistable behavior (where bistability is a phenomenon in which two stable steady states coexist for a fixed set of control parameter values) which here we suggest to be involved in the cell fate decision problem.
Physics Department, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil. lucianarenatadeoliveira@gmail.com.
L R
LR
de Oliveira
J C M
JC
Mombach
G
G
Castellani
D017209:Apoptosis; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004249:DNA Damage; D007700:Kinetics; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism; D015203:Reproducibility of Results; D013269:Stochastic Processes; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases