Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Abstract

Smad proteins are intracellular transducers for transforming growth factor-β (TGF-β signaling and play a critical role in differentiation, tissue repair and apoptosis of the central nervous system. Both TGF-β 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-3β 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-3β (GSK-3β), 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.

The Neuropeptide VGF Is Reduced in Human Bipolar Postmortem Brain and Contributes to Some of the Behavioral and Molecular Effects of Lithium

“…We have confirmed that LiCl (2 mM) induces increasing trends in phosphorylation of p42 MAPK (Tyr204), Akt (Ser473), and GSK3␤ (Ser9) in hippocampal cultures (Fig. 7 A, B) (Liang et al, 2008;Aubry et al, 2009) (Thakker-Varia et al, 2007), induced phosphorylation of p42 MAPK, Akt, and GSK3␤ to a similar degree as LiCl (Fig. 7 A, B In our hands, phospho-GSK3␣ (Ser21) and ␤-catenin levels were not significantly altered by either VGF or LiCl in hippocampal cultures (Fig.…”

“…Pooled tissue from each litter was mechanically dissociated in nutrient medium containing 7.5% fetal bovine serum and plated on poly-D-lysine-coated dishes at 350,000 cells per dish. Cultures were grown for 10 d in serum-free medium (ThakkerVaria et al, 2001), followed by treatment with VGF (3 M; Biopeptide), LiCl (2 mM; Sigma) (Liang et al, 2008), or PBS for 48 h. The dose of VGF was selected based on our previous in vitro studies (Thakker-Varia et al, 2007).…”

WNT/β-catenin increases the production of incretins by entero-endocrine cells

“…Lithium and WNT signalling inhibit GSK3β through accumulation of inactive phosphor-Ser21/Ser9 GSK3α/β [32]. Lithium also inhibits GSK3β competing with Mg 2+ [33] and additionally has a wide range of targets, reviewed in [34][35][36]. Therefore, we sought to confirm that endogenous mouse Gip and Gcg induction in STC-1 cells was mediated by mimicking canonical WNT/β-catenin pathway via GSK3β inhibition and not through alternative pathways (see below).…”

Inactivation of the Carney Complex Gene 1 (Protein Kinase A Regulatory Subunit 1A) Inhibits SMAD3 Expression and TGFβ-Stimulated Apoptosis in Adrenocortical Cells

“…The role of the TGFh pathway in adrenal cortex physiology led to the hypothesis that PRKAR1A inactivation might alter TGFh signaling, as there is cross-talk between cAMP and TGFh pathways. In keratinocytes and in cortical cells, the cAMP pathway abolishes the interaction of SMAD3 with the transcriptional coactivators CREB-binding protein and p300 (24,25). Here, PRKAR1A inactivation inhibits the mRNA and protein expression of SMAD3, a major distal component of the TGFh pathway.…”

“…TGFh may exert an antimitotic effect on human fetal adrenal cells in vitro (22,23). Moreover, previous studies suggested an interaction between cAMP/PKA and TGFh pathways (24,25).…”