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Tyson (1991), Modelling cell division

October 2006, model of the month by Nicolas Le Novère
Original model: BIOMD0000000005

One of the characteristics of life is autopoiesis, that is the auto-production. The biological cell is the archetypal example of an autopoietic systems. One of the key events of cell reproduction is the division of a cell into two descendants. In population formed of unicellular organisms, but also in many tissues of pluricellular organisms, this processus is a periodic one, called cell cycle. The mechanisms underlying eukaryotic cell cycle have been extensively studied, and have been found remarkably conserved throughout evolution. Their elucidation has been awarded the Nobel prize of physiology and medecine in 2001. Cell division is not only the basic mechanism by which a human is built from the egg, when altered it also triggers diseases such as cancers.

With his model published in 1991 [1], John Tyson played a pioneer role in what would become one of the most prolific fields of quantitative modeling in cell biology. One of the crucial events deciding the cell division is the formation of the Maturation Promoting Factor (MPF), from oscillating proteins called cyclin and specific protein kinases. With only 6 reacting species and 9 reactions (figure 1), Tyson built a mechanistic model explaining a very complex cellular behaviour from simple molecular events. The model is based on the creation and degradation of cyclin, its binding to and dissociation from cyclin dependent kinase CDC2, and the phosphorylation of both proteins. Although his model was primarily devoted to explain yeast cell cycle, its explanatory power covered the whole metazoa/fungi group.

reaction graph of Tyson1991 model typical result of Tyson1991 model
Figure 1: Reaction graph of the model from Tyson 1991. Figure 2: Oscillations of the total cyclin (YT) and the total MPF, relative to the total cyclin dependent kinase CDC2.

From this simple debut, Tyson's group went on building larger and more sophisticated models, some of them being present in BioModels Database, such as Novak and Tyson 1997 [2] (BIOMD0000000007) and Chen et al 2004 [3] (BIOMD0000000056). Several other groups developed models of cell cycle. Present in BioModels Database are the models described by Goldbeter 1991 [4] (BIOMD0000000003), Gardner et al 1998 [5] (BIOMD0000000008) and Fuss et al 2006 [6] (BIOMD0000000069).

Bibliographic References

  1. Tyson JJ. Modeling the cell division cycle: cdc2 and cyclin interactions. Proc Natl Acad Sci USA, 1991 Aug;88(16):7328-32. [PubMed]
  2. Novak B, Tyson JJ. Modeling the control of DNA replication in fission yeast. Proc Natl Acad Sci U S A 1997 Aug;94(17):9147-52. [PubMed]
  3. Chen KC, Calzone L, Csikasz-Nagy A, Cross FR, Novak B, Tyson JJ. Integrative analysis of cell cycle control in budding yeast. Mol Biol Cell 2004 Aug;15(8):3841-62. [PubMed]
  4. Goldbeter A. A minimal cascade model for the mitotic oscillator involving cyclin and cdc2 kinase. Proc Natl Acad Sci USA 1991 Oct;88(20):9107-11. [PubMed]
  5. Gardner TS, Dolnik M, Collins JJ. A theory for controlling cell cycle dynamics using a reversibly binding inhibitor. Proc Natl Acad Sci USA 1998 Nov;95(24):14190-5. [PubMed]
  6. Fuss H, Dubitzky W, Downes S, Kurth MJ. Bistable switching and excitable behaviour in the activation of Src at mitosis. Bioinformatics 2006 Jul;22(14):e158-65. [PubMed]