Regulation of the mammalian cell cycle: a model of the G1-to-S transition.
We have formulated a mathematical model for regulation of the G(1)-to-S transition of the mammalian cell cycle. This mathematical model incorporates the key molecules and interactions that have been identified experimentally. By subdividing these critical molecules into modules, we have been able to systematically analyze the contribution of each to dynamics of the G(1)-to-S transition. The primary module, which includes the interactions between cyclin E (CycE), cyclin-dependent kinase 2 (CDK2), and protein phosphatase CDC25A, exhibits dynamics such as limit cycle, bistability, and excitable transient. The positive feedback between CycE and transcription factor E2F causes bistability, provided that the total E2F is constant and the retinoblastoma protein (Rb) can be hyperphosphorylated. The positive feedback between active CDK2 and cyclin-dependent kinase inhibitor (CKI) generates a limit cycle. When combined with the primary module, the E2F/Rb and CKI modules potentiate or attenuate the dynamics generated by the primary module. In addition, we found that multisite phosphorylation of CDC25A, Rb, and CKI was critical for the generation of dynamics required for cell cycle progression.
Qu
Zhilin
Z
Cardiovascular Research Laboratory, Department of Medicine, University of California, Los Angeles, California 90095, USA. zqu@mednet.ucla.edu
Weiss
James N
JN
MacLellan
W Robb
WR
D000818:Animals; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005057:Eukaryotic Cells / Q000378:metabolism*; D005246:Feedback / Q000502:physiology; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D008322:Mammals / Q000502:physiology*; D017711:Nonlinear Dynamics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000378:metabolism
D018797:Cell Cycle Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases