title: A nontranscriptional role for Oct4 in the regulation of mitotic entry.
abstract: Rapid progression through the cell cycle and a very short G1 phase are defining characteristics of embryonic stem cells. This distinct cell cycle is driven by a positive feedback loop involving Rb inactivation and reduced oscillations of cyclins and cyclin-dependent kinase (Cdk) activity. In this setting, we inquired how ES cells avoid the potentially deleterious consequences of premature mitotic entry. We found that the pluripotency transcription factor Oct4 (octamer-binding transcription factor 4) plays an unappreciated role in the ES cell cycle by forming a complex with cyclin-Cdk1 and inhibiting Cdk1 activation. Ectopic expression of Oct4 or a mutant lacking transcriptional activity recapitulated delayed mitotic entry in HeLa cells. Reduction of Oct4 levels in ES cells accelerated G2 progression, which led to increased chromosomal missegregation and apoptosis. Our data demonstrate an unexpected nontranscriptional function of Oct4 in the regulation of mitotic entry.
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115;
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115; and.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Deibler
authors.affiliation: Department of Newborn Medicine and Department of Medicine, Division of Genetics, Brigham & Women's Hospital, Department of Medicine, Division of Newborn Medicine, Boston Children's Hospital, and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Lerou
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabeni
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115;
authors.forename: Garrett C
authors.initials: GC
authors.lastname: Heffner
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115;
authors.forename: Patrick
authors.initials: P
authors.lastname: Cahan
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115;
authors.forename: Juli J
authors.initials: JJ
authors.lastname: Unternaehrer
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115; and marc@hms.harvard.edu george.daley@childrens.harvard.edu.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Kirschner
authors.affiliation: Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115; marc@hms.harvard.edu george.daley@childrens.harvard.edu.
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D016193:G1 Phase / Q000502:physiology; D016195:G2 Phase / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D016213:Cyclins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C494174:Pou5f1 protein, mouse; D016160:Retinoblastoma Protein; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases
keywords: CDC25; Cdk1; Oct4; mitotic entry; pluripotent stem cells