Synergistic induction of cyclin D1 in oligodendrocyte progenitor cells by IGF‐I and FGF‐2 requires differential stimulation of multiple signaling pathways

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‐3β, 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‐3β 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. © 2007 Wiley‐Liss, Inc.