Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signalling in intact cells

Stambolic, Vuk; Ruel, Laurent; Woodgett, James R.

doi:10.1016/s0960-9822(02)70790-2

Cited by 1,248 publications

(1,017 citation statements)

References 35 publications

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“…Under these treatment conditions, lithium induced a concentration-dependent increase in the levels of phospho-GSK-3a Ser21 /b Ser9 (Figure 2d), thus indicating an inhibition of GSK-3 activity. 23,24,27 VPA treatment also markedly increased the levels of histone 3 acetylation with no apparent effects on the levels of HDAC1 isoform (Figure 2e), suggesting the inhibition of HDAC activity.…”

Section: Resultsmentioning

confidence: 94%

“…21,22 In the case of lithium-induced protection against glutamate-elicited neurotoxicity in cortical neurons, induction of BDNF is an obligatory event, as BDNF knockout or its receptor blockade prevents the neuroprotective effects of lithium. 21 Recent studies demonstrate that glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase consisting of two isoforms and regulating an array of transcription factors, is a direct target of lithium, 23,24 while VPA inhibits histone deacetylase (HDAC), which has a prominent role in the regulation of gene expression. 25,26 Emerging evidence suggests that inhibition of GSK-3 and HDAC are responsible, at least in part, for the neuroprotective effects of lithium and VPA, respectively.…”

Section: Introductionmentioning

confidence: 99%

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The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

et al. 2007

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Brain-derived neurotrophic factor (BDNF) has been strongly implicated in the synaptic plasticity, neuronal survival and pathophysiology of depression. Lithium and valproic acid (VPA) are two primary mood-stabilizing drugs used to treat bipolar disorder. Treatment of cultured rat cortical neurons with therapeutic concentrations of LiCl or VPA selectively increased the levels of exon IV (formerly rat exon III)-containing BDNF mRNA, and the activity of BDNF promoter IV. Surprisingly, lithium-or VPA-responsive element(s) in promoter IV resides in a region upstream from the calcium-responsive elements (CaREs) responsible for depolarization-induced BDNF induction. Moreover, activation of BDNF promoter IV by lithium or VPA occurred in cortical neurons depolarized with KCl, and deletion of these three CaREs did not abolish lithium-or VPA-induced activation. Lithium and VPA are direct inhibitors of glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC), respectively. We showed that lithium-induced activation of promoter IV was mimicked by pharmacological inhibition of GSK-3 or short interfering RNA (siRNA)-mediated gene silencing of GSK-3a or GSK-3b isoforms. Furthermore, treatment with other HDAC inhibitors, sodium butyrate and trichostatin A, or transfection with an HDAC1-specific siRNA also activated BDNF promoter IV. Our study demonstrates for the first time that GSK-3 and HDAC are respective initial targets for lithium and VPA to activate BDNF promoter IV, and that this BDNF induction involves a novel responsive region in promoter IV of the BDNF gene. Our results have strong implications for the therapeutic actions of these two mood stabilizers.

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Section: Resultsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

et al. 2007

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“…In addition, the mammalian homologs of two ft (fat)-interacting proteins, GSK3 and b-catenin (arm), have previously been shown to also respond to lithium, as well as valproate treatment. 59 GSK3 is a direct target of lithium [60][61][62] and is a key regulator of the Wnt signaling pathway 63 (Figure 3). GSK3 phosphorylates b-catenin leading to ubiquitin-dependent degradation.…”

Section: Discussionmentioning

confidence: 99%

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

et al. 2006

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A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P = 0.0002, summary odds ratio = 2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative b-catenin binding sites. Expression of Fat, Catnb (b-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P = 0.027), and Catnb and Enah were significantly upregulated (P = 0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P = 0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.

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“…Glycogen synthase kinase-3 (GSK-3) is one of the targets directly inhibited by lithium (Klein and Melton, 1996;Stambolic et al, 1996). GSK-3 consists of α and β isoforms and is a key kinase involved in the regulation of an array of transcription factors (reviewed in Grimes and Jope, 2001a).…”

Section: Introductionmentioning

confidence: 99%

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

Liang¹,

Wendland²,

Chuang³

2008

Molecular and Cellular Neuroscience

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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.

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Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signalling in intact cells

Abstract: Li+ acts as a specific inhibitor of the GSK-3 family of protein kinases in vitro and in intact cells, and mimics Wingless signalling. This reveals a possible molecular mechanism of Li+ action on development and differentiation.

Cited by 1,248 publications

References 35 publications

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

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

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