a hybrid model of mammalian cell cycle regulation哺乳动物细胞周期调控的混合模型.pdfVIP

A Hybrid Model of Mammalian Cell Cycle Regulation 1 2 2 1 Rajat Singhania , R. Michael Sramkoski , James W. Jacobberger , John J. Tyson * 1 Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America, 2 Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America Abstract The timing of DNA synthesis, mitosis and cell division is regulated by a complex network of biochemical reactions that control the activities of a family of cyclin-dependent kinases. The temporal dynamics of this reaction network is typically modeled by nonlinear differential equations describing the rates of the component reactions. This approach provides exquisite details about molecular regulatory processes but is hampered by the need to estimate realistic values for the many kinetic constants that determine the reaction rates. It is difficult to estimate these kinetic constants from available experimental data. To avoid this problem, modelers often resort to ‘qualitative’ modeling strategies, such as Boolean switching networks, but these models describe only the coarsest features of cell cycle regulation. In this paper we describe a hybrid approach that combines the best features of continuous differential equations and discrete Boolean networks. Cyclin abundances are tracked by piecewise linear differential equations for cyclin synthesis and degradation. Cyclin synthesis is regulated by transcription factors whose activities are represented by discrete variables (0 or 1) and likewise for the activities of the ubiquitin-ligating enzyme complexes that govern cyclin degradation. The discrete