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Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):15768-73. doi: 10.1073/pnas.1417518111. Epub 2014 Oct 16.

A nontranscriptional role for Oct4 in the regulation of mitotic entry.

Author information

1
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;
2
Department of Systems Biology, Harvard Medical School, Boston, MA 02115; and.
3
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.
4
Department of Systems Biology, Harvard Medical School, Boston, MA 02115; and marc@hms.harvard.edu george.daley@childrens.harvard.edu.
5
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.

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.

KEYWORDS:

CDC25; Cdk1; Oct4; mitotic entry; pluripotent stem cells

PMID:
25324523
PMCID:
PMC4226071
DOI:
10.1073/pnas.1417518111
[Indexed for MEDLINE]
Free PMC Article

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