Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 44, Pages 15768-15773Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1417518111
Keywords
pluripotent stem cells; mitotic entry; Oct4; Cdk1; CDC25
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Funding
- NIH National Heart, Lung, and Blood Institute (NHLBI) Progenitor Cell Biology Consortium [UO1-HL100001]
- National Institute of Diabetes and Digestive and Kidney Diseases [R24DK092760]
- Alex's Lemonade Stand
- Doris Duke Medical Foundation
- Harvard Stem Cell Institute
- NIH [R01GM026875, R01GM039023, RC4GM096319, K99HD061981]
- Charles H. Hood Foundation
- NHLBI [T32HL007623]
- Microarray Core Facility at the Children's Hospital Boston [NIH-P50-NS40828, NIH-P30-HD18655]
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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.
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