Inhibition of GSK3β is a common event in neuroprotection by different survival factors

Chin, Paul C.; Majdzadeh, Nazanin; D’Mello, Santosh R.

doi:10.1016/j.molbrainres.2005.03.004

Cited by 126 publications

(82 citation statements)

References 33 publications

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“…Indeed, the protein kinases glycogen synthase kinase 3 (GSK3), JNK and p38, which promote NFAT nuclear export, [15][16][17] have all been shown to be activated in CGNs deprived of serum and KCl. 29,36,[39][40][41] Moreover, KCl deprivation should result in calcineurin inactivation by reducing voltage-gated calcium influx. Therefore, NFAT transcription factors should be highly phosphorylated and maintained in the cytoplasm of CGNs following serum/KCl deprivation.…”

Section: Discussionmentioning

confidence: 99%

Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17

et al. 2014

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Neuronal apoptosis induced by survival factor deprivation is strongly regulated at the transcriptional level. Notably, the nuclear factor of activated T cell (NFAT) transcription factors have an important role in the control of the survival/death fate of neurons. However, the mechanisms that regulate NFAT activity in response to apoptotic stimuli and the target genes that mediate their effect on neuronal apoptosis are mostly unknown. In a previous study, we identified Trim17 as a crucial E3 ubiquitin ligase that is necessary and sufficient for neuronal apoptosis. Here, we show that Trim17 binds preferentially SUMOylated forms of NFATc3. Nonetheless, Trim17 does not promote the ubiquitination/degradation of NFATc3. NFAT transcription factors are regulated by calcium/calcineurin-dependent nuclear-cytoplasmic shuttling. Interestingly, Trim17 reduced by twofold the calcium-mediated nuclear localization of NFATc3 and, consistent with this, halved NFATc3 activity, as estimated by luciferase assays and by measurement of target gene expression. Trim17 also inhibited NFATc4 nuclear translocation and activity. NFATc4 is known to induce the expression of survival factors and, as expected, overexpression of NFATc4 protected cerebellar granule neurons from serum/KCl deprivation-induced apoptosis. Inhibition of NFATc4 by Trim17 may thus partially mediate the proapoptotic effect of Trim17. In contrast, overexpression of NFATc3 aggravated neuronal death, whereas knockdown of NFATc3 protected neurons from apoptosis. This proapoptotic effect of NFATc3 might be due to a feedback loop in which NFATc3, but not NFATc4, induces the transcription of the proapoptotic gene Trim17. Indeed, we found that overexpression or silencing of NFATc3, respectively, increased or decreased Trim17 levels, whereas NFATc4 had no significant effect on Trim17 expression. Moreover, we showed that NFATc3 binds to the promoter of the Trim17 gene together with c-Jun. Therefore, our results describe a novel mechanism regulating NFAT transcription factors beyond the calcium/calcineurin-dependent pathway and provide a possible explanation for the opposite effects of NFATc3 and NFATc4 on neuronal apoptosis.

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Section: Discussionmentioning

confidence: 99%

Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17

et al. 2014

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“…As both axin types inhibit b-catenin, these findings further suggested to us that b-catenin is functionally induced. Finally, it has been reported that growing muscle features inactivation via serine-9 phosphorylation of the b-catenin inhibitor GSK3b (Chin et al 2005). If true with DHT treatment, such an observation would also suggest activation of b-catenin signaling.…”

Section: Androgenic Repression Of Axin and Axin2 In The Soleusmentioning

confidence: 95%

Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

Gentile¹,

Nantermet²,

Vogel³

et al. 2009

Journal of Molecular Endocrinology

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Androgens promote anabolism in the musculoskeletal system while generally repressing adiposity, leading to lean body composition. Circulating androgens decline with age, contributing to frailty, osteoporosis, and obesity; however, the mechanisms by which androgens modulate body composition are largely unknown. Here, we demonstrate that aged castrated rats develop increased fat mass, reduced muscle mass and strength, and lower bone mass. Treatment with testosterone or 5a-dihydrotestosterone (DHT) reverses the effects on muscle and adipose tissues while only aromatizable testosterone increased bone mass. During the first week, DHT transiently increased soleus muscle nuclear density and induced expression of IGF1 and its splice variant mechano growth factor (MGF) without early regulation of the myogenic factors MyoD, myogenin, monocyte nuclear factor, or myostatin. A genome-wide microarray screen was also performed to identify potential pro-myogenic genes that respond to androgen receptor activation in vivo within 24 h. Of 24 000 genes examined, 70 candidate genes were identified whose functions suggest initiation of remodeling and regeneration, including the type II muscle genes for myosin heavy chain type II and parvalbumin and the chemokine monocyte chemoattractant protein-1. Interestingly, Axin and Axin2, negative regulators of b-catenin, were repressed, indicating modulation of the b-catenin pathway. DHT increased total levels of b-catenin protein, which accumulated in nuclei in vivo. Likewise, treatment of C2C12 myoblasts with both IGF1Ea and MGF C-terminal peptide increased nuclear b-catenin in vitro. Thus, we propose that androgenic anabolism involves early downregulation of Axin and induction of IGF1, leading to nuclear accumulation of b-catenin, a pro-myogenic, anti-adipogenic stem cell regulatory factor.

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“…Lithium has been shown to compete with magnesium for binding to GSK-3β and thereby blocks enzyme activity, then, inorganic phosphate attaches to the enzyme, further inactivating it [11,14,15,[17][18][19][32][33][34]. Chemical agents of the indirubin family can also inhibit GSK-3β, such as indirubin-3′-monoxime, 5-iodo-(IMI), a specific inhibitor of the enzyme, which inhibits GSK-3β by competing with ATP for binding to the catalytic site [22].…”

Section: Commentmentioning

confidence: 99%

Inhibition of Glycogen Synthase Kinase-3β Improves Tolerance to Ischemia in Hypertrophied Hearts

Barillas

Friehs

Cao-Danh

et al. 2007

The Annals of Thoracic Surgery

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Background-Hypertrophied myocardium is more susceptible to ischemia/reperfusion injury, in part owing to impaired insulin-mediated glucose uptake. Glycogen synthase kinase-3β (GSK-3β) is a key regulatory enzyme in glucose metabolism that, when activated, phosphorylates/inactivates target enzymes of the insulin signaling pathway. Glycogen synthase kinase-3β is regulated upstream by Akt-1. We sought to determine whether GSK-3β is activated in ischemic hypertrophied myocardium owing to impaired Akt-1 function, and whether inhibition with lithium (Li) or indirubin-3′-monoxime,5-iodo-(IMI), a specific inhibitor, improves post-ischemic myocardial recovery by improving glucose metabolism.

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Inhibition of GSK3β is a common event in neuroprotection by different survival factors

Cited by 126 publications

References 33 publications

Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17

Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17

Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

Inhibition of Glycogen Synthase Kinase-3β Improves Tolerance to Ischemia in Hypertrophied Hearts

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