The Per2 negative feedback loop sets the period in the mammalian circadian clock mechanism.

TitleThe Per2 negative feedback loop sets the period in the mammalian circadian clock mechanism.
Publication TypeJournal Article
Year of Publication2007
AuthorsWilkins, AK, Barton, PI, Tidor, B
JournalPLoS Comput Biol
Date Published2007 Dec
KeywordsAnimals, Biological Clocks, Computer Simulation, Feedback, Humans, Models, Biological, Nuclear Proteins, Oscillometry, Period Circadian Proteins, Periodicity, Signal Transduction, Transcription Factors

Processes that repeat in time, such as the cell cycle, the circadian rhythm, and seasonal variations, are prevalent in biology. Mathematical models can represent our knowledge of the underlying mechanisms, and numerical methods can then facilitate analysis, which forms the foundation for a more integrated understanding as well as for design and intervention. Here, the intracellular molecular network responsible for the mammalian circadian clock system was studied. A new formulation of detailed sensitivity analysis is introduced and applied to elucidate the influence of individual rate processes, represented through their parameters, on network functional characteristics. One of four negative feedback loops in the model, the Per2 loop, was uniquely identified as most responsible for setting the period of oscillation; none of the other feedback loops were found to play as substantial a role. The analysis further suggested that the activity of the kinases CK1delta and CK1varepsilon were well placed within the network such that they could be instrumental in implementing short-term adjustments to the period in the circadian clock system. The numerical results reported here are supported by previously published experimental data.

Alternate JournalPLoS Comput. Biol.
PubMed ID18085817
PubMed Central IDPMC2134962
Grant ListP50 GM58762 / GM / NIGMS NIH HHS / United States
U54 CA112967 / CA / NCI NIH HHS / United States