title: The role of APC/C inhibitor Emi2/XErp1 in oscillatory dynamics of early embryonic cell cycles.
abstract: The early embryonic Xenopus cell cycles are characterized by alternating oscillations of Cyclin-dependent kinase-1 (Cdk1) and Anaphase Promoting Complex/Cyclosome (APC/C) activities. The early cycles before midblastula transition lack significant inhibitory Cdk1 phosphorylations and are driven by periodic accumulation of Cyclin B before M phase and its degradation by APC/C at the end of M phase. Both experiments and mathematical modelling suggest that while Cdk1:CycB phosphorylation activates APC/C, it inhibits its co-activator Cdc20 (Fizzy). These interactions create an amplified negative-feedback loop which is at the heart of all cell cycle oscillations. Recent experiments find that the APC/C inhibitor, Emi2/XErp1 is essential for large amplitude and short period Cyclin B oscillations during early divisions in the intact Xenopus embryo. This finding is counter-intuitive since larger amplitudes should come with slower cycle times. We explain this paradox by analysing the amplified negative feedback model extended with APC/C inhibition by Emi2. We show that Emi2 interferes with the intrinsic time-delay in APC/C activation and inactivation to increase the amplitude as well as shorten the period of Cyclin B oscillation.
authors.affiliation: Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, Oxford, UK.
authors.forename: P K
authors.initials: PK
authors.lastname: Vinod
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Tongli
authors.initials: T
authors.lastname: Zhang
authors.forename: Thomas U
authors.initials: TU
authors.lastname: Mayer
authors.forename: Bela
authors.initials: B
authors.lastname: Novak
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D064199:Cdc20 Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D044783:F-Box Proteins / Q000737:chemistry / Q000378:metabolism*; D008962:Models, Theoretical; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D043743:Ubiquitin-Protein Ligase Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014981:Xenopus / Q000254:growth & development / Q000378:metabolism; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D064199:Cdc20 Proteins; C577501:Cdc20 protein, Xenopus; D018797:Cell Cycle Proteins; D019926:Cyclin B; D044783:F-Box Proteins; C498166:FBXO43 protein, Xenopus; D029867:Xenopus Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D016203:CDC2 Protein Kinase; D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1