title: Constant regulation of both the MPF amplification loop and the Greatwall-PP2A pathway is required for metaphase II arrest and correct entry into the first embryonic cell cycle.
abstract: Recent results indicate that regulating the balance between cyclin-B-Cdc2 kinase, also known as M-phase-promoting factor (MPF), and protein phosphatase 2A (PP2A) is crucial to enable correct mitotic entry and exit. In this work, we studied the regulatory mechanisms controlling the cyclin-B-Cdc2 and PP2A balance by analysing the activity of the Greatwall kinase and PP2A, and the different components of the MPF amplification loop (Myt1, Wee1, Cdc25) during the first embryonic cell cycle. Previous data indicated that the Myt1-Wee1-Cdc25 equilibrium is tightly regulated at the G2-M and M-G1 phase transitions; however, no data exist regarding the regulation of this balance during M phase and interphase. Here, we demonstrate that constant regulation of the cyclin-B-Cdc2 amplification loop is required for correct mitotic division and to promote correct timing of mitotic entry. Our results show that removal of Cdc25 from metaphase-II-arrested oocytes promotes mitotic exit, whereas depletion of either Myt1 or Wee1 in interphase egg extracts induces premature mitotic entry. We also provide evidence that, besides the cyclin-B-Cdc2 amplification loop, the Greatwall-PP2A pathway must also be tightly regulated to promote correct first embryonic cell division. When PP2A is prematurely inhibited in the absence of cyclin-B-Cdc2 activation, endogenous cyclin-A-Cdc2 activity induces irreversible aberrant mitosis in which there is, first, partial transient phosphorylation of mitotic substrates and, second, subsequent rapid and complete degradation of cyclin A and cyclin B, thus promoting premature and rapid exit from mitosis.
authors.affiliation: Universités Montpellier 2 et 1, Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, IFR 122, 1919 Route de Mende, 34293 Montpellier CEDEX 5, France. thierry.lorca@crbm.cnrs.fr
authors.forename: Thierry
authors.initials: T
authors.lastname: Lorca
authors.forename: Cyril
authors.initials: C
authors.lastname: Bernis
authors.forename: Suzanne
authors.initials: S
authors.lastname: Vigneron
authors.forename: Andrew
authors.initials: A
authors.lastname: Burgess
authors.forename: Estelle
authors.initials: E
authors.lastname: Brioudes
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Labbé
authors.forename: Anna
authors.initials: A
authors.lastname: Castro
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D019925:Cyclin A / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000166:cytology* / Q000502:physiology*; D016200:Maturation-Promoting Factor / Q000378:metabolism*; D008677:Metaphase / Q000502:physiology*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D029867:Xenopus Proteins / Q000378:metabolism*; D014982:Xenopus laevis; D020687:cdc25 Phosphatases / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019926:Cyclin B; D016200:Maturation-Promoting Factor; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D029867:Xenopus Proteins; D020687:cdc25 Phosphatases; C095970:MYT1 kinase, Xenopus; C530005:WEE1 protein, Xenopus; C544010:MASTL protein, Xenopus; C101085:Plk1 protein, Xenopus; D000097869:Polo-Like Kinase 1