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CREB DNA binding activity is inhibited by glycogen synthase kinase‐3β and facilitated by lithium
Author(s) -
Grimes Carol A.,
Jope Richard S.
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00495.x
Subject(s) - creb , gsk 3 , glycogen synthase , gsk3b , cyclic amp response element binding protein , chemistry , protein kinase a , microbiology and biotechnology , protein kinase b , lithium (medication) , phosphorylation , beta (programming language) , forskolin , biology , endocrinology , biochemistry , transcription factor , receptor , gene , computer science , programming language
The regulatory influences of glycogen synthase kinase‐3β (GSK3β) and lithium on the activity of cyclic AMP response element binding protein (CREB) were examined in human neuroblastoma SH‐SY5Y cells. Activation of Akt (protein kinase B) with serum‐increased phospho‐serine‐9‐GSK3β (the inactive form of the enzyme), inhibited GSK3β activity, and increased CREB DNA binding activity. Inhibition of GSK3β by another paradigm, treatment with the selective inhibitor lithium, also increased CREB DNA binding activity. The inhibitory regulation of CREB DNA binding activity by GSK3β also was evident in differentiated SH‐SY5Y cells, indicating that this regulatory interaction is maintained in non‐proliferating cells. These results demonstrate that inhibition of GSK3β by serine‐9 phosphorylation or directly by lithium increases CREB activation. Conversely, overexpression of active GSK3β to 3.5‐fold the normal levels completely blocked increases in CREB DNA binding activity induced by epidermal growth factor, insulin‐like growth factor‐1, forskolin, and cyclic AMP. The inhibitory effects due to overexpressed GSK3β were reversed by treatment with lithium and with another GSK3β inhibitor, sodium valproate. Overall, these results demonstrate that GSK3β inhibits, and lithium enhances, CREB activation.