Researchers develop mammalian cell cycle model
The cell division process plays an important role for single-cell and multi-cell organisms, especially for transforming fertilised eggs into mature organisms. Failure to control the cell cycle can result in tumour proliferation and cancer development. Researchers from Université Libre de Bruxelles (ULB) in Belgium have developed a detailed dynamics model of the mammalian cell cycle. The findings, published in the Proceedings of the National Academy of Sciences (PNAS) journal, will help raise awareness of the cell cycle's role in the pathology and normal functioning of living organisms. The research is part of the EU-funded BIOSIM ('Biosimulation - a new tool in drug development') project, which received almost EUR 11 million under the 'Life sciences, genomics and biotechnology for health' Thematic area of the EU's Sixth Framework Programme (FP6). BIOSIM is coordinated by the Technical University of Denmark, and includes partners from Belgium, Germany, Spain, France, Hungary, the Netherlands, Slovakia, Sweden and the UK. According to the researchers, data obtained over the last 20 years have indicated that the cell cycle is controlled by a cyclin-dependent kinases (Cdks) protein network. 'Progression in the cell cycle is controlled by the sequential, transient activation of a family of Cdks, which allow an ordered succession of the cell cycle phases, even though there appears to be a certain overlapping of the different cyclins and Cdks,' the authors of the study wrote. 'The Cdk proteins are active only when forming a complex with their corresponding cyclin.' The ULB researchers, however, determined that because of the complexity of the regulation process of the Cdk network and the difficulty in predicting its evolution, computer simulations of ideal behaviour models would provide the answers scientists have been looking for. ULB PhD student Claude Gérard developed the very detailed model signifying the dynamics of the mammalian cell cycle. 'The model contains four Cdk modules regulated by reversible phosphorylation, Cdk inhibitors, and protein synthesis or degradation,' the research showed. 'Growth factors (GFs) trigger the transition from a quiescent, stable steady state to self-sustained oscillations in the Cdk network. These oscillations correspond to the repetitive, transient activation of cyclin D/Cdk4-6 in G1, cyclin E/Cdk2 at the G1/S transition, cyclin A/Cdk2 in S and at the S/G2 transition, and cyclin B/Cdk1 at the G2/M transition.' The team highlighted how the model predicts that in the presence of suprathreshold amounts of growth factor the regulatory interactions within the Cdk network can suddenly generate sustained oscillations that correspond to the controlled and repetitive activation of the different cyclin/Cdk complexes along the cell cycle process. 'The present results suggest that the sequential activation of the Cdk modules in the Cdk network is brought about by temporal self-organisation corresponding to the global, periodic operation of the mammalian cell cycle,' the authors noted.
Countries
Belgium, Germany, Spain, France, Hungary, Netherlands, Sweden, Slovakia, United Kingdom