On Friday October 30 2015 at 3 PM Matteo Barberis will give the 4th SILS/IBED Systems Biology seminar entitled Deciphering design principles of dynamics cell cycle control. The lecture is at Science Park 904 in room C1.110. You are all welcome!
Abstract of the Seminar
Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, The Netherlands
The eukaryotic cell cycle is robustly designed, with networks of interacting molecules organized in functional modules and regulatory motifs to ensure precise timing of phase transitions. These phases are governed by waves of activity associated to enzymatic complexes, called cyclin/Cdk kinases, which rise and fall at a specific timing throughout cell cycle progression (1,2). However, it is not understood how and which cyclin/Cdk activators and inhibitors (3,4) are balanced to maintain this temporal coordination.
In this talk I will present a framework that integrates computational modelling – qualitative and dynamic ODE-based – and detailed experimentation – ranging from protein-protein interactions to live cell imaging to kinetic measurements – with the aim to unravel network motifs responsible for the temporal dynamics of cyclin/Cdk1 complexes in budding yeast. Dynamic modelling is performed under a quasi-steady state assumption, which implies a fast equilibrium of complex formation among activators/inhibitors. Robustness of network wiring is then investigated, with respect to the observed cyclin/Cdk1 oscillations.
A minimal model of cell cycle regulation embedding functional activatory and inhibitory modules is able to reproduce the waves of cyclins (5), and network motifs have to strike a balance to generate oscillations. Furthermore, cyclin/Cdk1-mediated phosphorylation kinetics on these substrates suggest how regulatory motifs may be coupled to generate timely cyclin waves.
This systems biology approach identifies regulatory modules that modulate the timing of cyclin/Cdk activities, and suggests a conserved, functional design principle of cell cycle control (6).
1. Futcher B. Cyclins and the wiring of the yeast cell cycle. Yeast 1996; 12:1635–46.
2. Nasmyth K. Control of the yeast cell cycle by the Cdc28 protein kinase. Curr Opin Cell Biol. 1993; 5:166–179.
3. Barberis M, De Gioia L, Ruzzene M, Sarno S, Coccetti P, Fantucci P, Vanoni M, Alberghina L. The yeast cyclin-dependent kinase inhibitor Sic1 and mammalian p27Kip1 are functional homologues with a structurally conserved inhibitory domain. Biochem J. 2005; 387:639-47.
4. Linke C, Klipp E, Lehrach H, Barberis M, Krobitsch S. Fkh1 and Fkh2 associate with Sir2 to control CLB2 transcription under normal and oxidative stress conditions. Front Physiol. 2013; 4:173.
5. Barberis M, Linke C, Adrover MÀ, González-Novo A, Lehrach H, Krobitsch S, Posas F, Klipp E. Sic1 plays a role in timing and oscillatory behaviour of B-type cyclins. Biotechnol Adv. 2012; 30:108-30.
6. Barberis M. Sic1 as a timer of Clb cyclin waves in the yeast cell cycle–design principle of not just an inhibitor. FEBS J. 2012; 279:3386-410.