A Nontranscriptional Role for Oct4 in the Regulation of Mitotic Entry

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2014 Oct 18

PMID 25324523

Citations 23

Authors

Rui Zhao

Richard W Deibler

Paul H Lerou

Andrea Ballabeni

Garrett C Heffner

Patrick Cahan

Juli J Unternaehrer

Marc W Kirschner

George Q Daley

Affiliations

Soon will be listed here.

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.

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References

Rosenblatt J, Gu Y, MORGAN D . Human cyclin-dependent kinase 2 is activated during the S and G2 phases of the cell cycle and associates with cyclin A. Proc Natl Acad Sci U S A. 1992; 89(7):2824-8. PMC: 48755. DOI: 10.1073/pnas.89.7.2824. View

Bortner D, Rosenberg M . Overexpression of cyclin A in the mammary glands of transgenic mice results in the induction of nuclear abnormalities and increased apoptosis. Cell Growth Differ. 1995; 6(12):1579-89. View

Guo Y, Mantel C, Hromas R, Broxmeyer H . Oct-4 is critical for survival/antiapoptosis of murine embryonic stem cells subjected to stress: effects associated with Stat3/survivin. Stem Cells. 2007; 26(1):30-4. PMC: 2818886. DOI: 10.1634/stemcells.2007-0401. View

Leonhardt H, Rahn H, Weinzierl P, Sporbert A, Cremer T, Zink D . Dynamics of DNA replication factories in living cells. J Cell Biol. 2000; 149(2):271-80. PMC: 2175147. DOI: 10.1083/jcb.149.2.271. View

Fenech M . Cytokinesis-block micronucleus cytome assay. Nat Protoc. 2007; 2(5):1084-104. DOI: 10.1038/nprot.2007.77. View

Scholer H, Dressler G, Balling R, Rohdewohld H, Gruss P . Oct-4: a germline-specific transcription factor mapping to the mouse t-complex. EMBO J. 1990; 9(7):2185-95. PMC: 551941. DOI: 10.1002/j.1460-2075.1990.tb07388.x. View

Lukas C, Sorensen C, Kramer E, Santoni-Rugiu E, Lindeneg C, Peters J . Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex. Nature. 1999; 401(6755):815-8. DOI: 10.1038/44611. View

Koff A, Giordano A, Desai D, Yamashita K, Harper J, Elledge S . Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science. 1992; 257(5077):1689-94. DOI: 10.1126/science.1388288. View

Heald R, McLoughlin M, McKeon F . Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated Cdc2 kinase. Cell. 1993; 74(3):463-74. DOI: 10.1016/0092-8674(93)80048-j. View

10.

Deibler R, Kirschner M . Quantitative reconstitution of mitotic CDK1 activation in somatic cell extracts. Mol Cell. 2010; 37(6):753-67. PMC: 2882237. DOI: 10.1016/j.molcel.2010.02.023. View

11.

Park I, Zhao R, West J, Yabuuchi A, Huo H, Ince T . Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2007; 451(7175):141-6. DOI: 10.1038/nature06534. View

12.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

13.

Fong Y, Inouye C, Yamaguchi T, Cattoglio C, Grubisic I, Tjian R . A DNA repair complex functions as an Oct4/Sox2 coactivator in embryonic stem cells. Cell. 2011; 147(1):120-31. PMC: 3216680. DOI: 10.1016/j.cell.2011.08.038. View

14.

Gong D, Ferrell Jr J . The roles of cyclin A2, B1, and B2 in early and late mitotic events. Mol Biol Cell. 2010; 21(18):3149-61. PMC: 2938381. DOI: 10.1091/mbc.E10-05-0393. View

15.

Savatier P, Lapillonne H, van Grunsven L, Rudkin B, Samarut J . Withdrawal of differentiation inhibitory activity/leukemia inhibitory factor up-regulates D-type cyclins and cyclin-dependent kinase inhibitors in mouse embryonic stem cells. Oncogene. 1996; 12(2):309-22. View

16.

Savatier P, Huang S, Szekely L, Wiman K, Samarut J . Contrasting patterns of retinoblastoma protein expression in mouse embryonic stem cells and embryonic fibroblasts. Oncogene. 1994; 9(3):809-18. View

17.

Li L, Wang J, Hou J, Wu Z, Zhuang Y, Lu M . Cdk1 interplays with Oct4 to repress differentiation of embryonic stem cells into trophectoderm. FEBS Lett. 2012; 586(23):4100-7. DOI: 10.1016/j.febslet.2012.10.030. View

18.

Manning A, Longworth M, Dyson N . Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev. 2010; 24(13):1364-76. PMC: 2895196. DOI: 10.1101/gad.1917310. View

19.

Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K . Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell. 2008; 1(1):55-70. DOI: 10.1016/j.stem.2007.05.014. View

20.

Becker K, Ghule P, Therrien J, Lian J, Stein J, van Wijnen A . Self-renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase. J Cell Physiol. 2006; 209(3):883-93. DOI: 10.1002/jcp.20776. View