Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling.
Smad proteins are intracellular transducers for transforming growth factor-beta (TGF-beta) signaling and play a critical role in differentiation, tissue repair and apoptosis of the central nervous system. Both TGF-beta and its regulated gene, plasminogen activator inhibitor type-1 (PAI-1), have been implicated in the etiology and progression of neurodegenerative diseases and mood disorders. We previously reported that GSK-3beta protein depletion suppresses Smad3/4-dependent gene transcription and causes a reduction in PAI-1 expression. Here, we provide evidence that lithium, the drug for the treatment and prophylaxis of bipolar disorder, inhibits Smad-dependent signaling by regulating cAMP-protein kinase A (PKA), AKT-glycogen synthase kinase-3beta (GSK-3beta), and CRE-dependent signaling pathways in neuron-enriched cerebral cortical cultures of rats. We demonstrate that lithium-induced activation of these pathways inhibits Smad3/4-dependent gene transcription through an increase in pCREB(Ser133) protein levels, an enhanced interaction between pCREB(Ser133) and p300/CBP, which causes Smad3/4-p300/CBP complex disruption and transcriptional suppression of Smad3/4-dependent genes. Therapeutic implications of our findings are discussed.
Liang
Min-Huei
MH
Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, 10 Center Dr. MSC 1363, Bethesda, MD, USA.
Wendland
Jens R
JR
Chuang
De-Maw
DM
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D047369:Chromatin Immunoprecipitation; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051900:Smad3 Protein / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection
D004791:Enzyme Inhibitors; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D050882:CREB-Binding Protein; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D018021:Lithium Chloride