Phosphatidylinositol 3-kinase activity is required for the expression of glial fibrillary acidic protein upon cAMP-dependent induction of differentiation in rat C6 glioma

Glial fibrillary acidic protein (GFAP) is an intermediate filament (IF) pro tein expressed upon maturation of astrocytes and upregulated during reactiv e astrogliosis. Its expression is modulated by several growth factors and h ormones. Although an upregulation of intracellular cAMP is required for the induction of GFAP expression in astrocytes, little information is availabl e on other downstream factors of the signal transduction pathways involved in the regulation of its expression. In this communication, we identified p hosphatidylinositol 3-kinase (PI 3-K) as a necessary enzyme for GFAP expres sion in rat C6 glioma cells. Use of the specific PI 3-K inhibitors wortmann in and LY294002 and transfection of C6 cells with a dominant negative PI 3- K construct, resulting in a decrease of the enzymatic activity of PI 3-K, i nhibited the cAMP-dependent expression of GFAP. Furthermore, confocal laser scanning microscopy demonstrated that inhibition of the PI 3-K activity by LY294002 or wortmannin concomitant with induction of differentiation chang es the cellular distribution leading to a pericentrosomal localization of G FAP and an altered cell shape lacking process formation. We conclude that t he expression and cellular distribution of GFAP is mediated through a PI 3- K-dependent mechanism.