IBM and NeSC workshop on Protein Science
National e-Science Centre, Edinburgh, March
15-16 2002
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A molecular blueprint of cell cycle control in yeast Lilia Alberghina§, Riccardo Rossi§, Simone Paleari§*, Matteo Barberis§, Luca DiGioia§, Antonio Giorgilli*, Piercarlo Fantucci§ and Marco Vanoni§. §Departments of Biotechnology and Biosciences and of *Mathematics, Università di Milano-Bicocca Milano, Italy. e-mail: lilia.alberghina@unimib.it An important challenge for the post-genomic era is to develop rational approaches to deal with data coming from high throughput technologies so to structure them in mathematical models able to describe complex cellular processes and to accurately predict their behavior. The yeast Saccharomyces cerevisiae has a completely sequenced genome consisting of about 6000 genes. Transcription of at least 400-500 gene has been shown to be cell cycle regulated and an increasing number of protein/protein interaction of key cell cycle proteins is being uncovered. To develop a molecular blueprint of the cell cycle control even of this simple model organism is therefore a significant task. A systems biology approach to the problem proposes that at Start a growth-sensitive cell sizer threshold (Ps) controls both the entrance into S phase and the sequential activation of cyclin-dependent kinases. The cycle is terminated by an End function whose major rate-limiting steps (entrance into and exit from mitosis) are also growth-regulated. Steady and transitory states of yeast populations during nutritional shift-up and hyperactivation of cAMP signalling are faithfully predicted by the model (Alberghina et al., Oncogene 2001 20:1128-34). This paper describes experiments aimed at the identification of the molecular determinants of the threshold Ps and at the development of computational methods to validate the model. The analysis of cell-based data compared to the results of simulations is indicative of putative mechanisms to be identified by genetic or metabolic modulations. Following this experimental approach, the role in Start of cyclins Cln3, Cln1 and 2, Clb5 and 6 and of the cyclin kinase dependent inhibitors Far1 and Sic1 (whose 3D structure in complex with Clb5 and Cdk1 has been determined by computational methods) is enriched of unexpected features. A matemathical model of the molecular blueprint of the events of Start has then been derived and used to develop a computational program. The model is being validated by simulation experiments run for different growth conditions and different genetic backgrounds. Taken together the present findings are a first test of the feasibility of a systems biology approach aimed to understand cell cycle control at the molecular level. Together with analysis of transcriptional profiles, protein/protein interaction maps and focused structure/function studies of key regulatory proteins, this approach will ultimately lead to the construction of a yeast e-cell that would give functional structure to genomic and post-genomic findings. |
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