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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 volume 21, pages 5515–5528 (2002)Cite this article

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.

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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).

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  1. Laboratoire de Biologie Moléculaire et Cellulaire, CNRS UMR 5665, INRA LA913, Ecole Normale Supérieure de Lyon, 46 allée d'Italie, Lyon, Cedex 07, 69364, France

    Ludmila Jirmanova, Marielle Afanassieff, Suzy Markossian & Pierre Savatier

  2. Centre de Génétique Moléculaire et Cellulaire, CNRS UMR 5534, Université Claude Bernard Lyon I, 43 boulevard du 11 novembre 1918, Villeurbanne Cedex, 69622, France

    Stéphanie Gobert-Gosse

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  1. Ludmila Jirmanova
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Correspondence to Pierre Savatier.

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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

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