β-Catenin Mediates Insulin-Like Growth Factor-I Actions to Promote Cyclin D1 mRNA Expression, Cell Proliferation and Survival In Oligodendroglial Cultures

By promoting cell proliferation, survival and maturation insulin-like growth factor (IGF)-I is essential to the normal growth and development of the central nervous system. It is clear that IGF-I actions are primarily mediated by the type I IGF receptor (IGF1R), and that phosphoinositide 3 (PI3)-Akt kinases and MAP kinases signal many of IGF-I-IGFIR actions in neural cells, including oligodendrocyte lineage cells. The precise downstream targets of these signaling pathways, however, remain to be defined. We studied oligodendroglial cells to determine whether beta-catenin, a molecule that is a downstream target of glycogen synthase kinase-3 beta (GSK3 beta) and plays a key role in the Wnt canonical signaling pathway, mediates IGF-I actions. We found that IGF-I increases p-catenin protein abundance within an hour after IGF-I-induced phosphorylation of Akt and GSK3 beta. Inhibiting the PI3-Akt pathway suppressed IGF-I-induced increases in p-catenin and cyclin D1 mRNA, while suppression of GSK3 beta activity simulated IGF-I actions. Knocking-down p-catenin mRNA by RNA interference suppressed IGF-I-stimulated increases in the abundance of cyclin D1 mRNA, cell proliferation, and cell survival. Our data suggest that p-catenin is an important downstream molecule in the PI3-Akt-GSK3 beta pathway, and as such it mediates IGF-I upregulation of cyclin D1 mRNA and promotion of cell proliferation and survival in oligodendroglial cells. (C) 2010 Wiley-Liss, Inc.