Steady states and oscillations in the p53/Mdm2 network.
p53 is activated in response to events compromising the genetic integrity of a cell. Recent data show that p53 activity does not increase steadily with genetic damage but rather fluctuates in an oscillatory fashion. Theoretical studies suggest that oscillations can arise from a combination of positive and negative feedbacks or from a long negative feedback loop alone. Both negative and positive feedbacks are present in the p53/Mdm2 network, but it is not known what roles they play in the oscillatory response to DNA damage. We developed a mathematical model of p53 oscillations based on positive and negative feedbacks in the p53/Mdm2 network. According to the model, the system reacts to DNA damage by moving from a stable steady state into a region of stable limit cycles. Oscillations in the model are born with large amplitude, which guarantees an all-or-none response to damage. As p53 oscillates, damage is repaired and the system moves back to a stable steady state with low p53 activity. The model reproduces experimental data in quantitative detail. We suggest new experiments for dissecting the contributions of negative and positive feedbacks to the generation of oscillations.
Ciliberto
Andrea
A
Molecular Network Dynamics Research Group of Hungarian Academy of Sciences, Budapest University of Technology and Economics, Budapest, Hungary.
Novak
Béla
B
Tyson
John J
JJ
D000818:Animals; D002453:Cell Cycle; D004249:DNA Damage; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D016366:Open Reading Frames; D009991:Oscillometry; D011518:Proto-Oncogene Proteins / Q000737:chemistry; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2