title: CDC6 controls dynamics of the first embryonic M-phase entry and progression via CDK1 inhibition.
abstract: CDC6 is essential for S-phase to initiate DNA replication. It also regulates M-phase exit by inhibiting the activity of the major M-phase protein kinase CDK1. Here we show that addition of recombinant CDC6 to Xenopus embryo cycling extract delays the M-phase entry and inhibits CDK1 during the whole M-phase. Down regulation of endogenous CDC6 accelerates the M-phase entry, abolishes the initial slow and progressive phase of histone H1 kinase activation and increases the level of CDK1 activity during the M-phase. All these effects are fully rescued by the addition of recombinant CDC6 to the extracts. Diminution of CDC6 level in mouse zygotes by two different methods results in accelerated entry into the first cell division showing physiological relevance of CDC6 in intact cells. Thus, CDC6 behaves as CDK1 inhibitor regulating not only the M-phase exit, but also the M-phase entry and progression via limiting the level of CDK1 activity. We propose a novel mechanism of M-phase entry controlled by CDC6 and counterbalancing cyclin B-mediated CDK1 activation. Thus, CDK1 activation proceeds with concomitant inhibition by CDC6, which tunes the timing of the M-phase entry during the embryonic cell cycle.
authors.affiliation: CNRS UMR 6092, Cell Cycle Team, Rennes, France; Université Rennes 1, Institut de Génétique et Développement de Rennes (IGDR), Rennes, France.
authors.forename: Mohammed
authors.initials: M
authors.lastname: El Dika
authors.affiliation: CNRS UMR 6092, Cell Cycle Team, Rennes, France; Université Rennes 1, Institut de Génétique et Développement de Rennes (IGDR), Rennes, France.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Laskowska-Kaszub
authors.affiliation: Warsaw University, Institute of Zoology, Embryology Department, Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Koryto
authors.affiliation: CNRS UMR 6092, Cell Cycle Team, Rennes, France; Université Rennes 1, Institut de Génétique et Développement de Rennes (IGDR), Rennes, France.
authors.forename: Damian
authors.initials: D
authors.lastname: Dudka
authors.affiliation: CNRS UMR 6092, Cell Cycle Team, Rennes, France; Université Rennes 1, Institut de Génétique et Développement de Rennes (IGDR), Rennes, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Prigent
authors.affiliation: CNRS UMR 6092, Cell Cycle Team, Rennes, France; Université Rennes 1, Institut de Génétique et Développement de Rennes (IGDR), Rennes, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Tassan
authors.affiliation: The Methodist Hospital Research Institute, 6670 Bertner Ave, Houston, TX 77030, USA.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kloc
authors.affiliation: Jagiellonian University, Genetics & Evolution Department, Cracow, Poland.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Polanski
authors.affiliation: Warsaw University, Institute of Zoology, Embryology Department, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Borsuk
authors.affiliation: CNRS UMR 6092, Cell Cycle Team, Rennes, France; Université Rennes 1, Institut de Génétique et Développement de Rennes (IGDR), Rennes, France. Electronic address: jacek.kubiak@univ-rennes1.fr.
authors.forename: Jacek Z
authors.initials: JZ
authors.lastname: Kubiak
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D002474:Cell-Free System; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D019926:Cyclin B / Q000502:physiology; D004261:DNA Replication; D004789:Enzyme Activation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005982:Glutathione Transferase / Q000378:metabolism; D051379:Mice; D008938:Mitosis; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D029867:Xenopus Proteins / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C502132:CDC6 protein, mouse; C118388:Cdc6 protein, Xenopus; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D019926:Cyclin B; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D029867:Xenopus Proteins; C069741:norcantharidin; D005982:Glutathione Transferase; D011494:Protein Kinases; C102333:histone H1 kinase; D016203:CDC2 Protein Kinase
keywords: CDC6; CDK1; Cell-free extract; Embryo; M-phase entry; Mouse zygote; NCTD; Xenopus laevis