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  • Original Paper
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Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin A/E and E2F activities

Oncogene volume 21, pages 8320–8333 (2002)Cite this article

Abstract

Pluripotent cells of embryonic origin proliferate at unusually rapid rates and have a characteristic cell cycle structure with truncated gap phases. To define the molecular basis for this we have characterized the cell cycle control of murine embryonic stem cells and early primitive ectoderm-like cells. These cells display precocious Cdk2, cyclin A and cyclin E kinase activities that are conspicuously cell cycle independent. Suppression of Cdk2 activity significantly decreased cycling times of pluripotent cells, indicating it to be rate-limiting for rapid cell division, although this had no impact on cell cycle structure and the establishment of extended gap phases. Cdc2-cyclin B was the only Cdk activity that was identified to be cell cycle regulated in pluripotent cells. Cell cycle regulation of cyclin B levels and Y15 regulation of Cdc2 contribute to the temporal changes in Cdc2-cyclin B activity. E2F target genes are constitutively active throughout the cell cycle, reflecting the low activity of pocket proteins such as p107 and pRb and constitutive activity of pRb-kinases. These results show that rapid cell division cycles in primitive cells of embryonic origin are driven by extreme levels of Cdk activity that lack normal cell cycle periodicity.

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References

  • Beddington RSP, Robertson EJ . 1989 Development 105: 733–737

  • Bradley A, Evans M, Kaufman M, Robertson E . 1984 Nature 309: 255–256

  • Brook FA, Gardner RL . 1997 Proc. Natl. Acad. Sci. USA 94: 5709–5712

  • Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ . 1999 EMBO J. 18: 1571–1583

  • Chisholm JC, Johnson MH, Warren PD, Fleming TP, Pickering SJ . 1985 J. Embryol. Exp. Morphol. 86: 311–336

  • Dhingra UH, Shirai H, Takehana Y, Wovkulich PM, Yabuki N . 1998 US patent # 5811420 (F Hoffmann-La Roche A-G Switz)

  • Doetschman TC, Eistetter H, Katz M, Schmidt W, Kemler R . 1985 J. Embryol. Exp. Morph. 87: 27–45

  • Dyson N . 1998 Genes Dev. 12: 2245–2262

  • Edgar BA, Lehner CF . 1996 Science 274: 1646–1652

  • Evans MJ, Kaufman MH . 1981 Nature 292: 154–156

  • Gabrielli BG, Clarke JM, McCormack AK, Ellem KAO . 1997 J. Biol. Chem. 272: 28607–28614

  • Gardner RL, Rossant J . 1979 J. Embryol. Exp. Morphol. 52: 141–152

  • Gardner RL, Beddington RSP . 1988 J. Cell Sci. Suppl 10: 11–27

  • Geng Y, Whoriskey W, Park MY, Medema RH, Li T, Weinberg RA, Sicinski P . 1999 Cell 97: 767–777

  • Gray-Bablin J, Zalvide J, Fox MP, Knickerbocker CJ, DeCaprio JA, Keyomarsi K . 1996 Proc. Natl. Acad. Sci. USA 93: 15215–15220

  • Guadagno TM, Newport JW . 1996 Cell 84: 73–82

  • Haas K, Johannes C, Geisen C, Schmidt T, Karsunky H, Blass-Kampmann S, Obe G, Moroy T . 1997 Oncogene 15: 2615–2623

  • Harwell RM, Porter DC, Danes C, Keyomarsi K . 2000 Cancer Res. 60: 481–489

  • Haub O, Goldfarb M . 1991 Development 112: 397–406

  • Hebert JM, Basilico C, Goldfarb M, Haub O, Martin GR . 1990 Dev. Biol. 138: 454–463

  • Helin K . 1998 Curr. Opin. Genet. Dev. 8: 28–35

  • Hogan BLM, Beddington RSB, Constantini F, Lacy E . 1994 Manipulating the mouse embryo 2nd edn Cold Spring Harbor Laboratory Press

    Google Scholar 

  • Hosler BA, LaRosa GJ, Grippo JF, Gudas L . 1989 Mol. Cell. Biol. 9: 5623–5629

  • Hu B, Mitra J, van den Heuvel S, Enders GH . 2001 Mol. Cell. Biol. 21: 2755–2766

  • Humbert PO, Rogers C, Ganiatsas S, Landsberg RL, Trimarchi JM, Dandapani S, Brugman C, Erdman S, Schrenzal M, Bronson RT, Lees JA . 2000 Mol. Cell. 6: 281–291

  • Hurford Jr RK, Cobrinik D, Lee MH, Dyson N . 1997 Genes Dev. 11: 1447–1463

  • Ikeda M-A, Jakoi L, Nevins JR . 1996 Proc. Natl. Acad. Sci. USA 93: 3215–3220

  • Keyomarsi K, Conte D, Toyofuku W, Fox MP . 1995 Oncogene 11: 941–950

  • Knoblich JA, Sauer K, Jones L, Richardson H, Saint R, Lehner CF . 1994 Cell 77: 1–20

  • Kranenburg O, de Groot RP, Van der Eb AJ, Zantema A . 1995 Oncogene 10: 87–95

  • Krek W, Ewen ME, Shirodkar S, Arany Z, Kaelin Jr WG, Livingstone DM . 1994 Cell 78: 161–172

  • Lake J, Rathjen J, Remiszewski J, Rathjen PD . 2000 J. Cell Biol. 113: 555–566

  • MacAuley A, Werb Z, Mirkes PE . 1993 Development 117: 873–883

  • Martin GR . 1981 Proc. Natl. Acad. Sci. USA 78: 7634–7636

  • Meijer L, Kim S-H . 1997 Methods Enzym. 283: 113–128

  • Mumberg D, Haas K, Moroy T, Niedenthal R, Hegemann JH, Funk M, Muller R . 1996 Oncogene 13: 2493–2497

  • Mummery CL, van den Brink CE, de Laat SW . 1987a Dev. Biol. 121: 10–19

  • Mummery CL, van Rooijen MA, van den Brink SE, de Laat SW . 1987b Cell Differ. 20: 153–160

  • Murray AW, Kirschner MW . 1989 Nature 333: 275–280

  • Murray AW, Hunt T . 1993 The Cell Cycle New York: WH Freeman

    Google Scholar 

  • Nichols J, Evans EP, Smith AG . 1990 Development 110: 1341–1348

  • Nielsen NH, Emdin S, Cajander J, Landberg G . 1997 Oncogene 14: 295–304

  • Nurse P . 1990 Nature 344: 503–508

  • Nurse P . 2000 Cell 100: 71–78

  • Ohtsubo M, Roberts JM . 1993 Science 259: 1908–1912

  • Pease S, Braghetta P, Gearing D, Grail D, Williams L . 1990 Dev. Biol. 141: 344–352

  • Pederson RA . 1994 Reprod. Fertil. Dev. 6: 543–552

  • Pelton TA, Bettess MD, Lake J, Rathjen PD . 1998 Reprod. Fertil. Dev. 10: 535–549

  • Power M-A, Tam PPL . 1993 Anat. Embryol. 187: 493–504

  • Rathjen PD, Nichols J, Toth S, Edwards DR, Heath JK, Smith AG . 1990 Genes Dev. 4: 2308–2318

  • Rathjen J, Lake JA, Bettess MD, Washington JM, Chapman G, Rathjen PD . 1999 J. Cell Sci. 112: 601–612

  • Rempel RE, Sleight SB, Maller JL . 1995 J. Biol. Chem. 270: 6843–6855

  • Resnick JL, Bixler LS, Cheng L, Donovan PJ . 1992 Nature 359: 550–551

  • Resnitzky D, Gossen M, Bujard H, Reed SI . 1994 Mol. Cell. Biol. 14: 1669–1679

  • Robertson E, Bradley A, Kuehn M, Evans M . 1986 Nature 323: 445–448

  • Robertson EJ . 1987 Teratocarcinomas and embryonic stem cells: A practical approach Robertson EJ (ed) Oxford: IRL Press pp. 71–112

    Google Scholar 

  • Rogers MB, Hosler BA, Gudas LJ . 1991 Development 113: 815–824

  • Savatier P, Huang S, Szekely L, Wiman KG, Samarut J . 1994 Oncogene 9: 809–818

  • Savatier P, Lapillonne H, van Grunsven LA, Rudkin BB, Samarut J . 1995 Oncogene 12: 309–322

  • Scholer HR, Dressler GR, Balling R, Rohdewohld H, Gruss P . 1990 EMBO J. 9: 2185–2195

  • Sherr CJ . 1993 Cell 73: 1059–1065

  • Sherr CJ . 1996 Science 274: 1672–1677

  • Sherr CJ, Roberts JM . 1999 Genes Dev. 13: 1501–1512

  • Smith A, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M, Rogers D . 1988 Nature 336: 688–690

  • Smith AG . 1991 J. Tiss. Cult. Meth. 13: 89–94

  • Snow MHL . 1977 J. Embryol. Exp. Morph. 42: 293–303

  • Solter D, Skreb N, Damjanov I . 1971 Exp. Cell Res. 64: 331–334

  • Spruck CH, Kwang-Ai W, Reed SI . 1999 Nature 401: 297–300

  • Sweeney C, Murphy M, Kubelka M, Ravnik SE, Hawkins CF, Wolgemuth DJ, Carrington M . 1996 Development 122: 53–64

  • Thomas KR, Capecchi MR . 1987 Cell 51: 503–512

  • Wianny F, Real FX, Mummery CL, Van Rooijen M, Lahti J, Samarut J, Savatier P . 1998 Dev. Dyn. 12: 49–62

  • Williams RL, Hilton DJ, Pease S, Wilson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA, Gough N . 1988 Nature 336: 684–687

  • Wimmel A, Lucibello FC, Sewing A, Adolph S, Muller R . 1994 Oncogene 9: 995–997

  • Xu M, Sheppard KA, Peng CY, Yee AS, Piwnica-Worms H . 1994 Mol. Cell. Biol. 14: 8420–8431

  • Yarden A, Geiger B . 1996 Dev. Dyn. 206: 1–11

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Acknowledgements

E Stead and J White contributed equally to this work. We thank Peter Wovkulich for technical assistance, Brian Gabrielli for many useful discussions, Peter Cartwright for critical reading of the manuscript and Brian Gabrielli for the GST-Cdc25b expression construct. This work was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia and from the Australian Research Council (ARC) through the Centre for Molecular Genetics of Development. E Stead and J White were supported by Australian Post-Graduate Research Awards.

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  1. Department of Molecular Biosciences and Center for Molecular Genetics of Development, University of Adelaide, North Terrace, Adelaide, 5005, South Australia, Australia

    Elaine Stead, Josephine White, Renate Faast, Simon Conn, Sherilyn Goldstone, Joy Rathjen, Peter Rathjen & Stephen Dalton

  2. BresaGen-Luminis Cell Therapy Program, University of Adelaide, North Terrace, Adelaide, 5005, South Australia, Australia

    Stephen Dalton

  3. Hoffman La Roche, 340 Kingsland Street, Nutley, 07110, New Jersey, NJ, USA

    Urvashi Dhingra & Duncan Walker

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  1. Elaine Stead
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Correspondence to Stephen Dalton.

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Stead, E., White, J., Faast, R. et al. Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin A/E and E2F activities. Oncogene 21, 8320–8333 (2002). https://doi.org/10.1038/sj.onc.1206015

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