Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells

Abstract

Mouse embryonic stem (ES) cells are known to express D-type cyclins at very low levels and these levels increase dramatically during in vitro and in vivo differentiation. Here, we investigate some of the signalling pathways regulating expression of cyclin D1 and progression to S phase, the Ras/Extracellular signal-regulated protein kinase (ERK) pathway and the phosphatidylinositol 3-kinase (PI3-kinase) pathway. We demonstrate that ERK phosphorylation is fully dispensable for the regulation of cyclin D1 level and for the progression from G1 to S phase in ES cells. By contrast, PI3-kinase activity is required for both. Differentiation induced by retinoic acid results in the gain of ERK-dependent control of cyclin D1 expression and of S phase progression. Differentiation is also paralleled by an increase in PI3-kinase activity. This leads (a) to an increase in the p70 S6 kinase-dependent regulation of the steady-state level of cyclin D1, and (b) to a concomitant decrease in the GSK3β-dependent rate of cyclin D1 degradation. Altogether, these multiple pathways account for the dramatic increase in the level of cyclin D1 protein which parallels ES cell differentiation. Our studies suggest that PI3-kinase is an important regulator of the ES cell cycle and that its activity is not regulated by mitogen stimulation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Aktas H, Cai H, Cooper GM . 1997 Mol. Cell. Biol. 17: 3850–3857

  • Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, Pestell RG . 1995 J. Biol. Chem. 270: 23589–23597

  • Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P . 1997 Curr. Biol. 7: 261–269

  • Alt JR, Cleveland JL, Hannink M, Diehl JA . 2000 Genes Dev. 14: 3102–3114

  • Badache A, Hynes NE . 2001 Cancer Res. 61: 383–391

  • Balmanno K, Cook SJ . 1999 Oncogene 18: 3085–3097

  • Brennan P, Mehl AM, Jones M, Rowe M . 2002 Oncogene 21: 1263–1271

  • Brunn GJ, Williams J, Sabers C, Wiederrecht G, Lawrence Jr JC, Abraham RT . 1996 EMBO J. 15: 5256–5267

  • Burdon T, Stracey C, Chambers I, Nichols J, Smith A . 1999 Dev. Biol. 210: 30–43

  • Burgering BM, Coffer PJ . 1995 Nature 376: 599–602

  • Cheng AM, Saxton TM, Sakai R, Kulkarni S, Mbamalu G, Vogel W, Tortorice CG, Cardiff RD, Cross JC, Muller WJ, Pawson T . 1998a Cell 95: 793–803

  • Chomczynski P, Sacchi N . 1987 Anal. Biochem. 162: 156–159

  • Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA . 1995 Nature 378: 785–789

  • Dani C, Chambers I, Johnstone S, Robertson M, Ebrahimi B, Saito M, Taga T, Li M, Burdon T, Nichols J, Smith A . 1998 Dev. Biol. 203: 149–162

  • del Peso L, Gonzales-Garcia M, Page C, Herrera R, Nunez G . 1997 Science 278: 687–689

  • de Rooij L, Bos JL . 1997 Oncogene 14: 623–625

  • Diehl JA, Zindy F, Sherr CJ . 1997 Genes Dev. 11: 957–972

  • Diehl JA, Cheng M, Roussel MF, Sherr CJ . 1998 Genes Dev. 12: 3499–3511

  • Dijkers PF, Medema RH, Pals C, Banerji L, Thomas NS, Lam EW, Burgering BM, Raaijmakers JA, Lammers JW, Koenderman L, Coffer PJ . 2000 Mol. Cell. Biol. 20: 9138–9148

  • Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR . 1995 Proc. Natl. Acad. Sci. USA 92: 7686–7689

  • Fukada T, Ohtani T, Yoshida Y, Shirogane T, Nishida K, Nakajima K, Hibi M, Hirano T . 1998 EMBO J. 17: 6670–6677

  • Grewe M, Gansauge F, Schmid RM, Adler G, Seufferlein T . 1999 Cancer Res. 59: 3581–3587

  • Hashemolhosseini S, Nagamine Y, Morley SJ, Desrivières S, Mercep L, Ferrari S . 1998 J. Biol. Chem. 273: 14424–14429

  • Herber B, Truss M, Beato M, Muller R . 1994 Oncogene 9: 1295–1304

  • Kawasome H, Papst P, Webb S, Keller GM, Johnson GL, Gelfand EW, Terada N . 1998 Proc. Natl. Acad. Sci. USA 95: 5033–5038

  • Klein PS, Melton DA . 1996 Proc. Natl. Acad. Sci. USA 93: 8455–8459

  • Kulik G, Klippel A, Weber MJ . 1997 Mol. Cell Biol. 17: 1595–1606

  • Lavoie JN, L'Allemain G, Brunet A, Muller R, Pouyssegur J . 1996 J. Biol. Chem. 271: 20608–20616

  • Li DM, Sun H . 1998 Proc. Natl. Acad. Sci. USA 95: 15406–15411

  • Marshall C . 1999 Curr. Opin. Cell Biol. 11: 732–736

  • Moodie SA, Wolfman A . 1994 Trends Genet. 10: 44–48

  • Mountford P, Zevnik B, Duwel A, Nichols J, Li M, Dani C, Robertson M, Chambers I, Smith A . 1994 Proc. Natl. Acad. Sci. USA 91: 4303–4307

  • Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN, Rosen N . 1998 J. Biol. Chem. 273: 29864–29872

  • Murillo H, Huang H, Schmidt LJ, Smith DI, Tindall DJ . 2001 Endocrinology 142: 4795–4805

  • Negoro S, Oh H, Tone E, Kunisada K, Fujio Y, Walsh K, Kishimoto T, Yamauchi-Takihara K . 2001 Circulation 103: 555–561

  • Pearson RB, Dennis PB, Han JW, Williamson NA, Kozma SC, Wettenhall RE, Thomas G . 1995 EMBO J. 14: 5279–5287

  • Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G . 1998 Science 279: 707–710

  • Ramakrishnan M, Musa NL, Li J, Liu PT, Pestell RG, Hershenson MB . 1998 Am. J. Respir. Cell Mol. Biol. 18: 736–740

  • Ravenhall C, Guida E, Harris T, Koutsoubos V, Stewart A . 2000 Br. J. Pharmacol. 131: 17–28

  • 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 . 1996 Oncogene 12: 309–322

  • Savatier P, Lapillonne H, Jirmanova L, Vitelli L, Samarut J . 2002 Methods Mol. Biol. 185: 27–33

  • Schiemann WP, Bartoe JL, Nathanson NM . 1997 J. Biol. Chem. 272: 16631–16636

  • Schratt G, Weinhold B, Lundberg AS, Schuck S, Berger J, Schwarz H, Weinberg RA, Ruther U, Nordheim A . 2001 Mol. Cell Biol. 21: 2933–2943

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

  • Sinibaldi D, Wharton W, Turkson J, Bowman T, Pledger WJ, Jove R . 2000 Oncogene 19: 5419–5427

  • Stambolic V, Ruel L, Woodgett JR . 1996 Curr. Biol. 6: 1664–1668

  • Stewart AG, Harris T, Fernandes DJ, Schachte LC, Koutsoubos V, Guida E, Ravenhall CE, Vadiveloo P, Wilson JW . 1999 Mol. Pharmacol. 56: 1079–1086

  • Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, Gavrilova N, Mueller B, Liu X, Wu H . 1999 Proc. Natl. Acad. Sci. USA 96: 6199–6204

  • Sutherland C, Leighton IA, Cohen P . 1993 Biochem. J. 296: 15–19

  • Takahashi-Tezuka M, Yoshida Y, Fukada T, Ohtani T, Yamanaka Y, Nishida K, Nakajima K, Hibi M, Hirano T . 1998 Mol. Cell Biol. 18: 4109–4117

  • Treinies I, Paterson HF, Hooper S, Wilson R, Marshall CJ . 1999 Mol. Cell Biol. 19: 321–329

  • Van Engeland M, Ramaekers FC, Schutte B, Reutelingsperger CP . 1996 Cytometry 24: 131–139

  • Vlahos CJ, Matter WF, Hui KY, Brown RF . 1994 J. Biol. Chem. 269: 5241–5248

  • Watanabe G, Albanese C, Lee RJ, Reutens A, Vairo G, Henglein B, Pestell RG . 1998 Mol. Cell Biol. 18: 3212–3222

  • Weber JD, Raben DM, Phillips PJ, Baldassare JJ . 1997 Biochem. J. 326: 61–68

  • Williams MR, Arthur JSC, Balendran A, van der Kaay J, Poli V, Cohen P, Alessi DR . 2000 Curr. Biol. 10: 439–448

Download references

Acknowledgements

We are grateful to Dr Austin Smith for the gift of IOUD2 cells and to Dr Johannes Bos for the gift of GST–RBD cDNA. This work was supported by research grants from Association pour la Recherche sur le Cancer (Nos. 5571, 7602 and 5738) and from Comités Départementaux de l'Yonne, de l'Isère et du Rhône de la Ligue Contre le Cancer. L Jirmanova is a recipient of a fellowship from the Fondation pour la Recherche Médicale (FRM).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pierre Savatier.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jirmanova, L., Afanassieff, M., Gobert-Gosse, S. et al. Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells. Oncogene 21, 5515–5528 (2002). https://doi.org/10.1038/sj.onc.1205728

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205728

Keywords

This article is cited by

Search

Quick links