Dynamics of molecular regulatory networks
Co-workers: Dr. Bernhard Schmierer, Dr. Vinod, P.K., Paula Freire, Enuo He, Orsolya Kapuy, Yaseen Ladak, Ahmed Rattani, Maria Rosa Domingo Sananes, Attila Tóth
The living cell is a dynamical system of molecular interactions. Most of the physiological properties of the cell (movement, growth and division etc.) are determined by molecular networks rather than by a single molecule. These molecular networks are intrinsically dynamic and they determine how a cell changes in space and time. The understanding of the physiological consequences of these regulatory molecular networks requires computational methods. Our group uses mathematical modelling to build links between cell physiology and the wiring diagram of regulatory networks. The main focus of our research is the eukaryotic cell cycle control system (Fig. 1). The regulatory network controlling eukaryotic cell cycle progression centers around cyclin dependent protein-kinases (Cdk’s) and their regulatory subunits (cyclins). The activity of Cdk/cyclin complexes is regulated in general, by availability of cyclin subunits, phosphorylation of the Cdk subunit and by binding of a stoichiometric inhibitor.
Using nonlinear ordinary differential equations, we have built successful computer models for cell cycle control network of budding and fission yeasts, frog and fruit fly embryos, and human cells. These models accurately reproduce the physiological properties of normal cell division, and the bizarre properties of mutant cells that have been studied. The models also predict phenotypes of novel mutants and unintuitive properties (bistability, hysteresis etc.) of the cell cycle machinery (see Fig. 2). The models also explain how checkpoint mechanisms block the control system when completion of certain cell cycle events (e.g. DNA replication, mitosis) is compromised (Fig. 3). Recently we became also interested in how cell cycle controls gets modified during the meiotic cycle when DNA replication is followed by two nuclear divisions.
- Csikász-Nagy, A., Battogtokh, D., Chen, K.C., Novák, B. & Tyson, J.J. (2006): Analysis of a generic model of eukaryotic cell cycle regulation. Biophysical Journal 90, 4361-4379
- Queralt, E., Lehane., C., Novák, B., & Uhlmann, F. (2006): Downregulation of PP2ACdc55 phosphatase by separase initiates mitotic exit in budding yeast. Cell 125, 719-732
- Novák, B., Tyson, J.J., Gyõrffy, B. & Csikász-Nagy, A. (2007): Irreversible cell cycle transitions due to systems-level feedback. Nature Cell Biology 9, 724-728
- Castagnetti, S., Novák, B. & Nurse, P. (2007): Microtubules offset growth site from the cell centre in fission yeast. Journal of Cell Science 120, 2205-2213
- Calzone, L, Thieffry, D., Tyson, J.J. & Novák, B. (2007): Dynamical modeling of syncytial mitotic cycles in Drosophila embryos. Molecular Systems Biology 3, 131
Figure 1: Cell cycle regulation of cyclin dependent kinase (Cdk1) Cyclin-B (CycB) complex. The active Cdk1/CycB dimer can be inactivated by binding to an inhibitor (CKI) or by phosphorylation of the kinase subunit by Wee1. The inhibitory phosphate group is removed by Cdc25 phosphatase (Cdc25). Cdk1/CycB can also be inactivated by proteolysis of its cyclin partner, mediated by the anaphase-promoting complex (APC) in combination with Cdc20
Figure 2: A generic bifurcation diagram of the eukaryotic cell cycle control network. The steady state activity of the Cdk1/CycB complex (an indicator of the state of the control system) is plotted against 'cell size'
Figure 3: Bifurcations diagrams for checkpoint controls. The G1 checkpoint stabilizes the steady state with low Cdk1/CycB activity (top). The unreplicated or damaged DNA (G2 checkpoint) increases the range of Cdk1/CycB activity with intermediate values (middle). Spindle (or metaphase) checkpoint stabilizes the otherwise unstable state of mitosis (bottom)