Mathematical Biosciences and Engineering (MBE)

Regulation of modular Cyclin and CDK feedback loops by an E2F transcription oscillator in the mammalian cell cycle

Pages: 445 - 461, Volume 8, Issue 2, April 2011      doi:10.3934/mbe.2011.8.445

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Orit Lavi - Department of Mathematics, Bar Ilan University, Ramat Gan 52900, Israel (email)
Doron Ginsberg - Life Science Faculty, Bar Ilan University, Ramat Gan 52900, Ireland (email)
Yoram Louzoun - Department of Mathematics, Bar Ilan University, Ramat Gan 52900, Ireland (email)

Abstract: The cell cycle is regulated by a large number of enzymes and transcription factors. We have developed a modular description of the cell cycle, based on a set of interleaved modular feedback loops, each leading to a cyclic behavior. The slowest loop is the E2F transcription and ubiquitination, which determines the cycling frequency of the entire cell cycle. Faster feedback loops describe the dynamics of each Cyclin by itself. Our model shows that the cell cycle progression as well as the checkpoints of the cell cycle can be understood through the interactions between the main E2F feedback loop and the driven Cyclin feedback loops. Multiple models were proposed for the cell cycle dynamics; each with differing basic mechanisms. We here propose a new generic formalism. In contrast with existing models, the proposed formalism allows a straightforward analysis and understanding of the dynamics, neglecting the details of each interaction. This model is not sensitive to small changes in the parameters used and it reproduces the observed behavior of the transcription factor E2F and different Cyclins in continuous or regulated cycling conditions. The modular description of the cell cycle resolves the gap between cyclic models, solely based on protein-protein reactions and transcription reactions based models. Beyond the explanation of existing observations, this model suggests the existence of unknown interactions, such as the need for a functional interaction between Cyclin B and retinoblastoma protein (Rb) de-phosphorylation.

Keywords:  Biomathematics, stability, ODE, robustness, forced oscilators.
Mathematics Subject Classification:  Primary: 58F15, 58F17; Secondary: 53C35.

Received: April 2010;      Accepted: October 2010;      Available Online: April 2011.