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. 2002 Aug 15;21(36):5515-28. doi: 10.1038/sj.onc.1205728.


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 GSK3beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Blotting, Northern
  • Blotting, Western
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Differentiation / drug effects
  • Cyclin D1 / biosynthesis*
  • Embryo, Mammalian / cytology
  • Enzyme Inhibitors / pharmacology
  • G1 Phase / physiology*
  • Gene Expression Regulation
  • Glycogen Synthase Kinase 3
  • Immunosuppressive Agents / pharmacology
  • Mice
  • Mitogen-Activated Protein Kinases / physiology*
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphorylation
  • RNA, Messenger / metabolism
  • S Phase / physiology*
  • Sirolimus / pharmacology
  • Stem Cells / metabolism*
  • Tretinoin / pharmacology


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • RNA, Messenger
  • Cyclin D1
  • Tretinoin
  • Phosphatidylinositol 3-Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Glycogen Synthase Kinase 3
  • Sirolimus