Enhancement by lithium of cAMP-induced CRE/CREB-directed gene transcription conferred by TORC on the CREB basic leucine zipper domain

Ulrike Böer , Julia Eglins , Doris Krause , Susanne Schnell , Christof Schöfl , Willhart Knepel , Ulrike Böer (1)

1 Molecular Pharmacology

The molecular mechanism of action of lithium salts in the treatment of bipolar disorder is not well understood. As their therapeutic action requires chronic treatment, adaptive neuronal processes are suggested to be involved. The molecular basis of this are changes in gene expression regulated by transcription factors like the cAMP-responsive element (CRE) binding protein (CREB). CREB contains a transactivation domain, in which Ser-119 is phosphorylated upon activation, and a basic leucine zipper region (bZip). The bZip serves for CREB dimerization and DNA-binding but also contributes to CREB transactivation by recruiting the coactivator TORC (transducer of regulated CREB). Here, the effect of lithium on CRE/CREB-directed gene transcription was investigated. Electrically excitable cells were transfected with CRE/CREB-driven luciferase reporter genes. LiCl (6 mM or higher) induced an up to 4.7-fold increase in 8BrcAMP-stimulated CRE/CREB-directed transcription. This increase was not due to enhanced Ser-119-phosphorylation or DNA-binding of CREB. Also the known targets inositol-monophosphatase and glycogen-synthase-kinase 3β were not involved as specific GSK3β-inhibitors and inositol replenishment did not mimic and abolish, respectively, the effect of lithium. However, lithium no longer enhanced CREB activity when the CREB-bZip was deleted or the TORC binding site inside the CREB-bZip was specifically mutated (CREB-R300A). Otherwise, TORC overexpression conferred lithium responsiveness to CREB-bZip or the CRE-containing truncated rat somatostatin promoter. This indicates that lithium enhances cAMP-induced CRE/CREB-directed transcription, conferred by TORC to the CREB-bZip. We thus support the hypothesis that lithium salts modulate CRE/CREB-dependent gene transcription and suggest the CREB coactivator TORC as new molecular target of lithium.

Mots clés: Life Sciences

Ulrike Böer, Julia Eglins, Doris Krause, Susanne Schnell, Christof Schöfl, et al.. Enhancement by lithium of cAMP-induced CRE/CREB-directed gene transcription conferred by TORC on the CREB basic leucine zipper domain. Biochemical Journal, 2007, 408 (1), pp.69-77. ⟨10.1042/BJ20070796⟩. ⟨hal-00478826⟩