Abstract
D-type cyclins are direct targets of extracellular signals and critical regulators of G(1) progression. Our previous data demonstrated that IGF-I and FGF-2 synergize to enhance cyclin D1 expression, cyclin E/cdk2 complex activation, and S-phase entry in OP cells. Here, we provide a mechanistic explanation for how two growth factor signaling pathways converge on a major cell cycle regulator. IGF-I and FGF-2 differentially activate signaling pathways to coordinately promote cyclin D1 expression. We show that the p44/p42 MAPK signaling pathway is essential for FGF-2 induction of cyclin D1 mRNA. In contrast, blocking the PI3-Kinase pathway results in loss of IGF-I/FGF-2 synergistic induction of cyclin D1 protein levels. Moreover, the presence of IGF-I significantly enhances nuclear localization of cyclin D1, which also requires PI3K signaling. GSK-3beta, a downstream target of the PI3K/Akt pathway, is phosphorylated in the presence of IGF-I in OPs. Consistent with a known role for GSK-3beta in cyclin D1 degradation, we show that proteasome inhibition in OPs exposed to FGF-2 increased cyclin D1 levels, equivalent to levels seen in IGF-I/FGF-2 treated cells. Thus, we provide a model for cyclin D1 coordinate regulation where FGF-2 stimulation of the MAPK pathway promotes cyclin D1 mRNA expression while IGF-I activation of the PI3K pathway inhibits proteasome degradation of cyclin D1 and enhances nuclear localization of cyclin D1.
Copyright 2007 Wiley-Liss, Inc.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Active Transport, Cell Nucleus / drug effects
-
Active Transport, Cell Nucleus / physiology
-
Animals
-
Animals, Newborn
-
Cell Cycle / drug effects
-
Cell Cycle / physiology
-
Cell Differentiation / drug effects
-
Cell Differentiation / physiology
-
Cell Proliferation / drug effects
-
Cells, Cultured
-
Coculture Techniques
-
Cyclin D
-
Cyclins / drug effects
-
Cyclins / metabolism*
-
Drug Synergism
-
Fibroblast Growth Factor 2 / metabolism*
-
Fibroblast Growth Factor 2 / pharmacology
-
Glycogen Synthase Kinase 3 / drug effects
-
Glycogen Synthase Kinase 3 / metabolism
-
Glycogen Synthase Kinase 3 beta
-
Insulin-Like Growth Factor I / metabolism*
-
Insulin-Like Growth Factor I / pharmacology
-
MAP Kinase Signaling System / drug effects
-
MAP Kinase Signaling System / physiology
-
Models, Biological
-
Oligodendroglia / drug effects
-
Oligodendroglia / metabolism*
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphoinositide-3 Kinase Inhibitors
-
Phosphorylation / drug effects
-
Proteasome Endopeptidase Complex / drug effects
-
Proteasome Endopeptidase Complex / metabolism
-
Rats
-
Rats, Sprague-Dawley
-
Signal Transduction / drug effects
-
Signal Transduction / physiology*
-
Stem Cells / drug effects
-
Stem Cells / metabolism*
-
Up-Regulation / drug effects
-
Up-Regulation / physiology
Substances
-
Cyclin D
-
Cyclins
-
Phosphoinositide-3 Kinase Inhibitors
-
Fibroblast Growth Factor 2
-
Insulin-Like Growth Factor I
-
Glycogen Synthase Kinase 3 beta
-
Gsk3b protein, rat
-
Glycogen Synthase Kinase 3
-
Proteasome Endopeptidase Complex