Bifurcation analysis of the regulatory modules of the mammalian G1/S transition.
BACKGROUND
Mathematical models of the cell cycle can contribute to an understanding of its basic mechanisms. Modern simulation tools make the analysis of key components and their interactions very effective. This paper focuses on the role of small modules and feedbacks in the gene-protein network governing the G1/S transition in mammalian cells. Mutations in this network may lead to uncontrolled cell proliferation. Bifurcation analysis helps to identify the key components of this extremely complex interaction network.


RESULTS
We identify various positive and negative feedback loops in the network controlling the G1/S transition. It is shown that the positive feedback regulation of E2F1 and a double activator-inhibitor module can lead to bistability. Extensions of the core module preserve the essential features such as bistability. The complete model exhibits a transcritical bifurcation in addition to bistability. We relate these bifurcations to the cell cycle checkpoint and the G1/S phase transition point. Thus, core modules can explain major features of the complex G1/S network and have a robust decision taking function.
Swat
Maciej
M
Institute for Theoretical Biology, Humboldt University Berlin, Invalidenstrasse 43, Berlin, D-10115, Germany. swat@itb.biologie.hu-berlin.de
Kel
Alexander
A
Herzel
Hanspeter
H
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000378:metabolism; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005246:Feedback / Q000502:physiology*; D016193:G1 Phase / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D005809:Genes, Regulator / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D016196:S Phase / Q000502:physiology*; D012440:Saccharomyces / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013045:Species Specificity; D014157:Transcription Factors / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D014157:Transcription Factors