Restriction point control of the mammalian cell cycle via the cyclin E/Cdk2:p27 complex

被引：63

作者：

Conradie, Riaan ^{[1
]}

Bruggeman, Frank J. ^{[2
]}

Ciliberto, Andrea ^{[3
]}

Csikasz-Nagy, Attila ^{[4
]}

Novak, Bela ^{[5
]}

Westerhoff, Hans V. ^{[2
,6
]}

Snoep, Jacky L. ^{[1
,2
,6
]}

机构：

[1] Univ Stellenbosch, Triple J Grp Mol Cell Physiol, Dept Biochem, ZA-7602 Matieland, South Africa

[2] Vrije Univ Amsterdam, Mol Cell Physiol & Netherlands Inst Syst Biol, Amsterdam, Netherlands

[3] FIRC Inst Mol Oncol Fdn, Milan, Italy

[4] Univ Trento, Ctr Computat & Syst Biol, Povo, Trento, Italy

[5] Univ Oxford, Oxford Ctr Integrat Syst Biol, Oxford OX1 2JD, England

[6] Univ Manchester, Manchester Ctr Integrat Syst Biol, Manchester Interdisciplinary Bioctr, Manchester M13 9PL, Lancs, England

来源：

FEBS JOURNAL | 2010年 / 277卷 / 02期

基金：

英国工程与自然科学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

cell cycle; kinetic modeling; metabolic control analysis; restriction point; systems biology; METABOLIC-CONTROL ANALYSIS; INHIBITOR P27; EXPRESSION; NETWORKS; BIOLOGY; ADENOCARCINOMA; PROLIFERATION; SYSTEMS;

D O I：

10.1111/j.1742-4658.2009.07473.x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：357 / 367

页数：11

共 35 条

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