Rewiring the exit from mitosis.
The mitotic cell cycle can be described as an alternation between two states. During mitosis, MPF (mitosis promoting factor) is high and keeps inactive its numerous molecular antagonists. In interphase, MPF is inactivated, and the antagonists prevail. The transition between the two states is ensured by 'helper' molecules that favor one state over the other. It has long been assumed that active MPF (a dimer of cyclin B and cyclin-dependent kinase 1) induces exit from mitosis by activating APC:Cdc20, a ubiquitin ligase responsible for cyclin B degradation. The molecular details have not been fully worked out yet, but recent results show that MPF and the ubiquitin ligase are not involved in a simple negative feedback loop. While it is proven that MPF activates APC, new data suggest that MPF inhibits Cdc20, i.e., that MPF and Cdc20 are antagonists. We introduce this new idea into a published model for cell cycle regulation in Xenopus laevis, and study its dynamical behavior. We show that the new wiring permits oscillations with a simpler and smaller network than previously envisaged and that the antagonism between MPF and Cdc20 suggests a new interpretation of the spindle checkpoint.
Ciliberto
Andrea
A
Molecular Network Dynamics Research Group of Hungarian Academy of Sciences and Budapest University of Technology and Economics, Budapest, Hungary.
Lukács
Anna
A
Tóth
Attila
A
Tyson
John J
JJ
Novák
Béla
B
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D064199:Cdc20 Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D019281:Dimerization; D007700:Kinetics; D016200:Maturation-Promoting Factor / Q000378:metabolism*; D000090204:Mesothelin; D008938:Mitosis; D008954:Models, Biological; D008956:Models, Chemical; D008962:Models, Theoretical; D009991:Oscillometry; D010710:Phosphates / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D008941:Spindle Apparatus; D013997:Time Factors; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry; D014981:Xenopus; D029867:Xenopus Proteins / Q000502:physiology; D014982:Xenopus laevis / Q000378:metabolism
D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; D018797:Cell Cycle Proteins; D019926:Cyclin B; C000715528:Msln protein, mouse; D010710:Phosphates; D029867:Xenopus Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D044767:Ubiquitin-Protein Ligases; D016200:Maturation-Promoting Factor; D000090204:Mesothelin