CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium

The regulatory influences of glycogen synthase kinase-3 beta (GSK3 beta) an d lithium on the activity of cyclic AMP response element binding protein (C REB) were examined in human neuroblastoma SH-SY5Y cells. Activation of Akt (protein kinase B) with serum-increased phospho-serine-9-GSK3 beta (the ina ctive form of the enzyme), inhibited GSK3 beta activity, and increased CREB DNA binding activity. Inhibition of GSK3 beta by another paradigm, treatme nt with the selective inhibitor lithium, also increased CREB DNA binding ac tivity. The inhibitory regulation of CREB DNA binding activity by GSK3 beta also was evident in differentiated SH-SY5Y cells, indicating that this reg ulatory interaction is maintained in nonproliferating cells. These results demonstrate that inhibition of GSK3 beta by serine-9 phosphorylation or dir ectly by lithium increases CREB activation. Conversely, overexpression of a ctive GSK3 beta to 3.5-fold the normal levels completely blocked increases in CREB DNA binding activity induced by epidermal growth factor, insulin-li ke growth factor-1, forskolin, and cyclic AMP. The inhibitory effects due t o overexpressed GSK3 beta were reversed by treatment with lithium and with another GSK3 beta inhibitor, sodium valproate. Overall, these results demon strate that GSK3 beta inhibits, and lithium enhances, CREB activation.