Conradie2010_RPControl_CellCycle

ABSTRACT: This model is from the article: Restriction point control of the mammalian cell cycle via the cyclin E/Cdk2:p27 complex. Conradie R, Bruggeman FJ, Ciliberto A, Csikász-Nagy A, Novák B, Westerhoff HV, Snoep JL FEBS J.2010 Jan; 277(2): 357-67 20015233, Abstract: Numerous top-down kinetic models have been constructed to describe the cell cycle. These models have typically been constructed, validated and analyzed using model species (molecular intermediates and proteins) and phenotypic observations, and therefore do not focus on the individual model processes (reaction steps). We have developed a method to: (a) quantify the importance of each of the reaction steps in a kinetic model for the positioning of a switch point [i.e. the restriction point (RP)]; (b) relate this control of reaction steps to their effects on molecular species, using sensitivity and co-control analysis; and thereby (c) go beyond a correlation towards a causal relationship between molecular species and effects. The method is generic and can be applied to responses of any type, but is most useful for the analysis of dynamic and emergent responses such as switch points in the cell cycle. The strength of the analysis is illustrated for an existing mammalian cell cycle model focusing on the RP [Novak B, Tyson J (2004) J Theor Biol230, 563-579]. The reactions in the model with the highest RP control were those involved in: (a) the interplay between retinoblastoma protein and E2F transcription factor; (b) those synthesizing the delayed response genes and cyclin D/Cdk4 in response to growth signals; (c) the E2F-dependent cyclin E/Cdk2 synthesis reaction; as well as (d) p27 formation reactions. Nine of the 23 intermediates were shown to have a good correlation between their concentration control and RP control. Sensitivity and co-control analysis indicated that the strongest control of the RP is mediated via the cyclin E/Cdk2:p27 complex concentration. Any perturbation of the RP could be related to a change in the concentration of this complex; apparent effects of other molecular species were indirect and always worked through cyclin E/Cdk2:p27, indicating a causal relationship between this complex and the positioning of the RP. The rate constants presented in the paper have units [per tenth of an hour] and have been changed here to [per hour] (e.g. k16 = 0.25 not 0.025); for further confirmation of the correctness of this change, see the original model (Novak, J Theor Biol 2004 230:563).

SUBMITTER: Kieran Smallbone  

PROVIDER: BIOMD0000000265 | BioModels | 2010-07-20

REPOSITORIES: BioModels