Creb DNA binding activity is inhibited by glycogen synthase kinase-3β and facilitated by lithium

Carol A. Grimes, Richard S Jope

Research output: Contribution to journalArticle

292 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1219-1232
Number of pages14
JournalJournal of Neurochemistry
Volume78
Issue number6
DOIs
StatePublished - Oct 8 2001
Externally publishedYes

Fingerprint

Glycogen Synthase Kinase 3
Lithium
Cyclic AMP Response Element-Binding Protein
DNA
Protein Binding
Chemical activation
Serine
Proto-Oncogene Proteins c-akt
Phosphorylation
Valproic Acid
Somatomedins
Colforsin
Neuroblastoma
Epidermal Growth Factor
Cyclic AMP

Keywords

  • CREB
  • Glycogen synthase kinase-3β
  • Lithium
  • Valproate

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Creb DNA binding activity is inhibited by glycogen synthase kinase-3β and facilitated by lithium. / Grimes, Carol A.; Jope, Richard S.

In: Journal of Neurochemistry, Vol. 78, No. 6, 08.10.2001, p. 1219-1232.

Research output: Contribution to journalArticle

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