Dynamical analysis of a generic Boolean model for the control of the mammalian cell cycle

MOTIVATION To understand the behaviour of complex biological regulatory networks, a proper integration of molecular data into a full-fledge formal dynamical model is ultimately required. As most available data on regulatory interactions are qualitative, logical modelling offers an interesting framework to delineate the main dynamical properties of the underlying networks. RESULTS Transposing a generic model of the core network controlling the mammalian cell cycle into the logical framework, we compare different strategies to explore its dynamical properties. In particular, we assess the respective advantages and limits of synchronous versus asynchronous updating assumptions to delineate the asymptotical behaviour of regulatory networks. Furthermore, we propose several intermediate strategies to optimize the computation of asymptotical properties depending on available knowledge. AVAILABILITY The mammalian cell cycle model is available in a dedicated XML format (GINML) on our website, along with our logical simulation software GINsim (http://gin.univ-mrs.fr/GINsim). Higher resolution state transitions graphs are also found on this web site (Model Repository page).

[1]  R Thomas,et al.  Dynamical behaviour of biological regulatory networks--I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state. , 1995, Bulletin of mathematical biology.

[2]  Werner Dubitzky,et al.  Mathematical models of cell cycle regulation , 2005, Briefings Bioinform..

[3]  David Pellman,et al.  Activity of the APC Cdh 1 form of the anaphase-promoting complex persists until S phase and prevents the premature expression of Cdc 20 p , 2001 .

[4]  Stuart A. Kauffman,et al.  The origins of order , 1993 .

[5]  W. Pledger,et al.  Cell Cycle Control: A Complex Issue , 2004, Cell cycle.

[6]  D Thieffry,et al.  GINsim: a software suite for the qualitative modelling, simulation and analysis of regulatory networks. , 2006, Bio Systems.

[7]  David Pellman,et al.  Activity of the APCCdh1 form of the anaphase-promoting complex persists until S phase and prevents the premature expression of Cdc20p , 2001, The Journal of cell biology.

[8]  P. Bork,et al.  Dynamic Complex Formation During the Yeast Cell Cycle , 2005, Science.

[9]  L. Glass,et al.  The logical analysis of continuous, non-linear biochemical control networks. , 1973, Journal of theoretical biology.

[10]  Duanduan Ma,et al.  Exit from G1 and S Phase of the Cell Cycle Is Regulated by Repressor Complexes Containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF , 2000, Cell.

[11]  K. Helin,et al.  Regulation of cell proliferation by the E2F transcription factors. , 1998, Current opinion in genetics & development.

[12]  Adrien Richard,et al.  Application of formal methods to biological regulatory networks: extending Thomas' asynchronous logical approach with temporal logic. , 2004, Journal of theoretical biology.

[13]  Martine Labbé,et al.  Identification of all steady states in large networks by logical analysis , 2003, Bulletin of mathematical biology.

[14]  René Thomas.  Regulatory networks seen as asynchronous automata: A logical description , 1991 .

[15]  John J Tyson,et al.  A model for restriction point control of the mammalian cell cycle. , 2004, Journal of theoretical biology.

[16]  O. Coqueret,et al.  New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? , 2003, Trends in cell biology.

[17]  Ulrich Lehmann,et al.  Cell cycle and no end , 2004, Virchows Archiv.

[18]  J Wade Harper,et al.  The anaphase-promoting complex: it's not just for mitosis any more. , 2002, Genes & development.

[19]  E. Rubin,et al.  Role of pRB dephosphorylation in cell cycle regulation. , 2000, Frontiers in bioscience : a journal and virtual library.

[20]  Denis Thieffry,et al.  Petri net modelling of biological regulatory networks , 2008, J. Discrete Algorithms.

[21]  Denis Thieffry,et al.  Qualitative Analysis of Regulatory Graphs: A Computational Tool Based on a Discrete Formal Framework , 2003, POSTA.

[22]  Radu Mateescu,et al.  Validation of qualitative models of genetic regulatory networks by model checking: analysis of the nutritional stress response in Escherichia coli , 2005, ISMB.

[23]  N. Dyson,et al.  The E2F transcriptional network: old acquaintances with new faces , 2005, Oncogene.

[24]  D. Thieffry,et al.  Dynamical behaviour of biological regulatory networks—I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state , 1995 .

[25]  Marc W. Kirschner,et al.  Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry , 2004, Nature.

[26]  Madalena Chaves,et al.  Robustness and fragility of Boolean models for genetic regulatory networks. , 2005, Journal of theoretical biology.

[27]  Y Taya,et al.  RB kinases and RB-binding proteins: new points of view. , 1997, Trends in biochemical sciences.