Lithium stimulates gene expression through the AP-1 transcription factor pathway

Yuan, Pei-Xong; Chen, Guang; Huang, Li-Dong; Manji, Husseini K.

doi:10.1016/s0169-328x(98)00114-4

Cited by 66 publications

(56 citation statements)

References 23 publications

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“…Among possible mechanisms that might account for the reduced CD151 expression, altered RNA metabolism through various nuclear events, including rate of transcription, mRNA export, or mRNA degradation, merit further consideration. In this regard, several lines of evidence indicate that these mood stabilizers modulate c-fos mRNA levels (Miller and Mathe, 1997;Lee et al 2000), and DNA binding activity and/or protein levels of various transcription factors, such as CREB and AP-1 (Ozaki and Chuang 1997;Asghari et al 1998;Yuan et al 1998). These could potentially be involved in the regulation of CD151 expression.…”

Section: Discussionmentioning

confidence: 99%

“…5 et al 2000). The modulatory effects of lithium on gene expression have been suggested to be mediated, at least in part, through the cAMP response element binding protein (CREB) or activator protein-1 (AP-1) transcriptional factor pathway (Ozaki and Chuang 1997;Asghari et al 1998;Yuan et al 1998). It is thus conceivable that other genes containing the consensus sequences for these transcription factors in their promoter region may also be the potential targets of lithium.…”

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confidence: 99%

“…In line with this hypothesis, several studies have demonstrated that chronic lithium treatment alters the expression of an array of genes, including G protein ␣ -subunits, adenylyl cyclase subtypes, neuropeptides (reviewed in Jope 1999;Li et al 2000;Manji and Lenox 1999), proapoptotic and antiapoptotic proteins (Chen and Chuang 1999), and synaptic secretory vesicle proteins (Cordeiro et al 2000). The modulatory effects of lithium on gene expression have been suggested to be mediated, at least in part, through the cAMP response element binding protein (CREB) or activator protein-1 (AP-1) transcriptional factor pathway (Ozaki and Chuang 1997;Asghari et al 1998;Yuan et al 1998). It is thus conceivable that other genes containing the consensus sequences for these transcription factors in their promoter region may also be the potential targets of lithium.…”

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confidence: 99%

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Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

Hua

Green

Wong

et al. 2001

Neuropsychopharmacology

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The latency in onset of antimanic and mood stabilizing effects of lithium suggest that long-term neuronal adaptations mediated by changes in gene expression may be important to the therapeutic action of lithium treatment. Using differential display-polymerase chain reaction, several novel, hitherto unexpected lithium-regulated genes have been isolated, all of which would not have beenAlthough lithium is widely used in the treatment of acute mania and the prophylaxis for bipolar affective disorder, the cellular and molecular mechanisms underlying its therapeutic action remain unclear. However, significant progress has been made over the past decade with cumulative evidence indicating that modulation of postreceptor signaling mechanisms in critical regions of the brain may be essential to the mood stabilizing properties of this agent (reviewed in Jope 1999;Li et al. 2000;Manji and Lenox 1999).Many signal transduction cascades are known to induce long-term cellular responses through regulation of gene transcription. Moreover, the delayed onset of therapeutic action of lithium has led to the hypothesis that regulation of gene expression may be important for its mood stabilizing effects (Jope 1999;Li et al. 2000). In line with this hypothesis, several studies have demonstrated that chronic lithium treatment alters the expression of an array of genes, including G protein ␣ -subunits, adenylyl cyclase subtypes, neuropeptides (reviewed in Jope 1999;Li et al. 2000;Manji and Lenox 1999) NO . 5 et al. 2000). The modulatory effects of lithium on gene expression have been suggested to be mediated, at least in part, through the cAMP response element binding protein (CREB) or activator protein-1 (AP-1) transcriptional factor pathway (Ozaki and Chuang 1997;Asghari et al. 1998;Yuan et al. 1998). It is thus conceivable that other genes containing the consensus sequences for these transcription factors in their promoter region may also be the potential targets of lithium. Therefore, the identification of other lithium-regulated genes is important in better understanding the spectrum of cellular and molecular mechanisms that contribute to the therapeutic and/or side effects of this drug.Using differential display-polymerase chain reaction (ddPCR), several novel lithium-regulated genes have been identified that would not otherwise have been considered using a candidate gene approach. These novel lithium-regulated targets included 2 Ј , 3 Ј -cyclic nucleotide 3 Ј -phosphodiesterase type II (Wang and Young 1996), polyomavirus enhancer-binding protein 2 ␤ (Chen et al. 1999), nitrogen permease regulator 2 (Wang et al. 1999), aldolase A (Hua et al. 2000, and diphosphoinositol polyphosphate phosphohydrolase II (Hua et al. 2001). Unexpectedly, during the course of experiments amplifying the 5 Ј end of a putative lithium-regulated ddPCR fragment, we isolated another cDNA clone, a homolog of human/mouse transmembrane-4-superfamily (TM4SF) protein, CD151. The transcript levels of CD151 were significantly decreased in the rat frontal corte...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

Hua

Green

Wong

et al. 2001

Neuropsychopharmacology

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“…However, lithium, as well as valproic acid, were recently reported to elevate the basal, unstimulated AP-1 DNA binding activity, leading to the conclusion from the latter studies that anti-bipolar therapeutics activate AP-1. [8][9][10] Thus, these findings appeared to be directly contradictory, and it was difficult to discern whether lithium was increasing or decreasing the activity of this important transcription factor. However, as indicated in Figure 2, both actions of lithium can play complementary roles in contributing to stabilization of the magnitude in fluctuations in the activity of AP-1.…”

Section: Application Of the Model To Ap-1mentioning

confidence: 99%

A bimodal model of the mechanism of action of lithium

Jope

1999

Mol Psychiatry

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Investigations of the biochemical actions of lithium have identified many individual reactions that are affected, especially within cellular signaling systems, but the actions of lithium at different sites often appear opposing and difficult to integrate into a general mechanism of action. A bimodal mechanism of action of lithium is proposed which is in accord with many of the apparently contradictory results that have been published. This model describes the critical effect of lithium as that of a stabilizer of the magnitude of fluctuations of signaling processes. This is achieved by lithium balancing positive and negative regulators of signaling processes which results in lithium raising basal activities and diminishing maximal activities, thereby stabilizing signaling activities within an optimal range and preventing fluctuations either above or below this optimum. This model is shown to be applicable to many published results concerning the activation of AP-1 DNA binding and cyclic AMP production. Diverse sites of action of lithium are proposed to ultimately converge on the regulation of gene expression to contribute to mood stabilization.

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“…Among the many biochemical actions of long term lithium treatment in vivo and in vitro are its ability to inhibit phosphoinoside turnover and stimulated levels of calcium, influence signal transduction by modulating G-proteins and protein kinase C, and regulate gene expression involving AP-1 DNA binding activity (1)(2)(3)(4)(5)(6)(7). Increasing evidence supports the notion that lithium has neuroprotective effects.…”

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Long Term Lithium Treatment Suppresses p53 and Bax Expression but Increases Bcl-2 Expression

Chen

Chuang

1999

Journal of Biological Chemistry

442

265

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This study was undertaken to investigate the molecular mechanisms underlying the neuroprotective actions of lithium against glutamate excitotoxicity with a focus on the role of proapoptotic and antiapoptotic genes. Long term, but not acute, treatment of cultured cerebellar granule cells with LiCl induces a concentration-dependent decrease in mRNA and protein levels of proapoptotic p53 and Bax; conversely, mRNA and protein levels of cytoprotective Bcl-2 are remarkably increased. The ratios of Bcl-2/Bax protein levels increase by approximately 5-fold after lithium treatment for 5-7 days. Exposure of cerebellar granule cells to glutamate induces a rapid increase in p53 and Bax mRNA and protein levels with no apparent effect on Bcl-2 expression. Pretreatment with LiCl for 7 days prevents glutamate-induced increase in p53 and Bax expression and maintains Bcl-2 in an elevated state. Glutamate exposure also triggers the release of cytochrome c from the mitochondria into the cytosol. Lithium pretreatment blocks glutamate-induced cytochrome c release and cleavage of lamin B1, a nuclear substrate for caspase-3. These results strongly suggest that lithium-induced Bcl-2 up-regulation and p53 and Bax down-regulation play a prominent role in neuroprotection against excitotoxicity. Our results further suggest that lithium, in addition to its use in the treatment of bipolar depressive illness, may have an expanded use in the intervention of neurodegeneration.

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Lithium stimulates gene expression through the AP-1 transcription factor pathway

Cited by 66 publications

References 23 publications

Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

A bimodal model of the mechanism of action of lithium

Long Term Lithium Treatment Suppresses p53 and Bax Expression but Increases Bcl-2 Expression

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