Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.26 (GSK)
6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A model of fetal alcohol syndrome was used to investigate prenatal ethanol effects on cerebellar transcription factors. Pregnant Sprague-Dawley rats were divided into three treatment groups: ethanol-exposed (E), calorically matched pair-fed (PF), and freely fed ad libitum (AL) groups. Ethanol exposure was stopped 2 days before parturition. The DNA binding in neonatal cerebella of the redox-sensitive transcription factors nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1) were determined by electrophoretic mobility shift assays. On the first postnatal day (PD1), there was decreased activation of these transcription factors in the E group relative to the control groups. The PD1 transcriptional effects were reversed as the neonate underwent development without further ethanol exposure. Western blot studies showed no corresponding decreases in protein amounts of both AP-1 and NF-kappa B components on PD1. Postnatal glutathione levels and catalase activity, as measures of oxidative stress hypothesized to be a probable cause of the transcriptional effects, showed no statistically significant effects attributable to ethanol. Examination of prenatal cerebella on embryonic day 20 (EM20), a time during ethanol exposure, showed DNA-binding trends similar to those of PD1. EM20 Western blot studies showed decreases in the levels of the active form of glycogen synthase kinase-3 (GSK-3). GSK-3 inhibition was reversed by PD1. Blocking of GSK-3 activity with gestational dietary lithium diminished both AP-1 and NF-kappa B DNA binding. Thus, prenatal ethanol exposure has the effect of diminishing pro-survival transcriptional activation, an effect possibly mediated by changes in GSK-3 activity.
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PMID:In utero ethanol suppresses cerebellar activator protein-1 and nuclear factor-kappa B transcriptional activation in a rat fetal alcohol syndrome model. 1190 84

A potential mechanism underlying ethanol-induced alterations in gene expression is the disruption of transcription factor activity. Growth factor receptors, particularly receptor tyrosine kinases, play an important role in modulating many biological effects of ethanol. We demonstrated here that the expression of epidermal growth factor receptor (EGFR) mediated the effect of ethanol on the activity of transcription factor activator protein-1 (AP-1). Ethanol had little effect on AP-1 activity in the fibroblast cells devoid of EGFR (B82); however, it significantly suppressed AP-1 activity in B82 cells that were stably transfected with either a wild-type EGFR (B82L) or a kinase-deficient receptor (B82M721) in a concentration-dependent manner. EGF activated AP-1 only in B82L cells; the activation was mediated primarily by Akt and ERK. Ethanol inhibited EGF-induced EGFR autophosphorylation, phosphorylation of ERK as well as Akt and its substrate GSK-3beta, and subsequently blocked EGF-stimulated AP-1 activation in B82L cells. On the other hand, ethanol had little effect on EGF-stimulated JNK activation. Phorbol ester 12-O-teradecanoyl-phorbol-13-acetate (TPA) activated AP-1 in B82L and B82M721 cells, but not B82 cells. TPA-induced activation of ERK and PKCdelta was dependent on the expression of EGFR although the intrinsic kinase activity of EGFR was not required. In contrast, TPA-induced phosphorylation of p38 MAPK, JNKs and other PKC isoforms was independent of EGFR. Ethanol selectively inhibited TPA-induced phosphorylation of ERK and PKCdelta, and modestly suppressed TPA-stimulated AP-1 activation in B82L and B82M721 cells. Thus, EGFR plays a critical role in the interaction between ethanol and AP-1.
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PMID:The role of epidermal growth factor receptor in ethanol-mediated inhibition of activator protein-1 transactivation. 1587 57

Chronic and excessive alcohol consumption is an important and modifiable risk factor for type 2 diabetes. We previously reported elevations in hepatic Class 1 alcohol dehydrogenase (ADH) expression in ethanol-fed rats correspondent with reduced levels of mature, nuclear sterol-regulatory element-binding protein-1 (SREBP-1), an insulin-induced transcriptional repressor of the ADH gene. In this report, we have studied the effects of insulin and ethanol on ADH gene expression in a highly differentiated rat hepatoma cell line (FGC-4), as well as the in vivo effects of chronic intake of an ethanol-containing diet on hepatic insulin signaling. Insulin inhibited ADH gene expression, and this was abolished by LY294002 (a phosphatidylinositol 3-kinase inhibitor) and small interfering RNA knockdown of SREBP-1. Chronic ethanol intake led to decreased phosphorylation of Akt (protein kinase B) at Thr308, increased phosphorylation of Akt at Ser473, and decreased phosphorylation of glycogen synthase kinase-3beta (a downstream effector of Akt). Hepatic membrane-associated Akt content was decreased and cytosolic Akt content was increased in rats fed an ethanol-containing diet. Thus, disruptive effects of ethanol on insulin signaling occurred via impaired phosphorylation of Akt at Thr308. TRB3, a negative regulator of Akt, was induced in liver of ethanol-fed rats. In ethanol-treated FGC-4 cells, small interfering RNA knockdown of TRB3 increased membrane-associated Akt and the phosphorylation of Akt at Thr308. Our results suggest that ethanol induces TRB3, which, through binding to the pleckstrin homology domain of Akt, prevents its plasma membrane association, Akt-Thr308 phosphorylation, and subsequent Akt-mediated signaling. Ethanol inhibition of insulin signaling reduces nuclear SREBP accumulation and results in disinhibition of Class 1 ADH transcription.
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PMID:Chronic ethanol intake impairs insulin signaling in rats by disrupting Akt association with the cell membrane. Role of TRB3 in inhibition of Akt/protein kinase B activation. 1645 80

Lithium is widely used for the treatment of bipolar disorder. Recent studies have demonstrated its neuroprotective effect. Ethanol is a potent neurotoxin that is particularly harmful to the developing nervous system. In this study, we evaluated lithium's neuroprotection against ethanol-induced apoptosis. Transient exposure of infant mice to ethanol caused apoptotic cell death in brain, which was prevented significantly by administering a low dose of lithium 15min later. In cultured cerebellar granule neurons, ethanol-induced apoptosis and activation of caspase-3/9, both of which were prevented by lithium. However, lithium's protection is not mediated by its commonly known inhibition of glycogen synthase3beta, because neither ethanol nor lithium has significant effects on the phosphorylation of Akt (ser473) or GSK3beta (ser9). In addition, the selective GSK-3beta inhibitor SB-415286 was unable to prevent ethanol-induced apoptosis. These data suggest lithium may be used as a potential preventive measure for ethanol-induced neurological deficits.
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PMID:Lithium protects ethanol-induced neuronal apoptosis. 1704 45

Cerebellar hypoplasia in fetal alcohol spectrum disorders (FASD) is associated with inhibition of insulin and insulin-like growth factor (IGF) signaling in the brain. Aspartyl (asparaginyl)-beta-hydroxylase (AAH) is a mediator of neuronal motility, and stimulated by insulin and IGF activation of PI3 kinase-Akt, or inhibition of GSK-3beta. Since ethanol inhibits PI3 Kinase-Akt and increases GSK-3beta activity in brain, we examined the effects of ethanol and GSK-3beta on AAH expression and directional motility in neuronal cells. Control and ethanol-exposed (100 mM x 48 h) human PNET2 cerebellar neuronal cells were stimulated with IGF-1 and used to measure AAH expression and directional motility. Molecular and biochemical approaches were used to characterize GSK-3beta regulation of AAH and neuronal motility. Ethanol reduced IGF-1 stimulated AAH protein expression and directional motility without inhibiting AAH's mRNA. Further analysis revealed that: (1) AAH protein could be phosphorylated by GSK-3beta; (2) high levels of GSK-3beta activity decreased AAH protein; (3) inhibition of GSK-3beta and/or global Caspases increased AAH protein; (4) AAH protein was relatively more phosphorylated in ethanol-treated compared with control cells; and (5) chemical inhibition of GSK-3beta and/or global Caspases partially rescued ethanol-impaired AAH protein expression and motility. Ethanol-impaired neuronal migration is associated with reduced IGF-I stimulated AAH protein expression. This effect may be mediated by increased GSK-3beta phosphorylation and Caspase degradation of AAH. Therapeutic strategies to rectify CNS developmental abnormalities in FASD should target factors underlying the ethanol-associated increases in GSK-3beta and Caspase activation, e.g. IGF resistance and increased oxidative stress.
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PMID:Ethanol impaired neuronal migration is associated with reduced aspartyl-asparaginyl-beta-hydroxylase expression. 1847 38

Fetal alcohol spectrum disorder (FASD) is caused by prenatal exposure to alcohol and associated with hypoplasia and impaired neuronal migration in the cerebellum. Neuronal survival and motility are stimulated by insulin and insulin-like growth factor (IGF), whose signaling pathways are major targets of ethanol neurotoxicity. To better understand the mechanisms of ethanol-impaired neuronal migration during development, we examined the effects of chronic gestational exposure to ethanol on aspartyl (asparaginyl)-beta-hydroxylase (AAH) expression, because AAH is regulated by insulin/IGF and mediates neuronal motility. Pregnant Long-Evans rats were pair-fed isocaloric liquid diets containing 0, 8, 18, 26, or 37% ethanol by caloric content from gestation day 6 through delivery. Cerebella harvested from postnatal day 1 pups were used to examine AAH expression in tissue, and neuronal motility in Boyden chamber assays. We also used cerebellar neuron cultures to examine the effects of ethanol on insulin/IGF-stimulated AAH expression, and assess the role of GSK-3beta-mediated phosphorylation on AAH protein levels. Chronic gestational exposure to ethanol caused dose-dependent impairments in neuronal migration and corresponding reductions in AAH protein expression in developing cerebella. In addition, prenatal ethanol exposure inhibited insulin and IGF-I-stimulated directional motility in isolated cerebellar granule neurons. Ethanol-treated neuronal cultures (50mMx96h) also had reduced levels of AAH protein. Mechanistically, we showed that AAH protein could be phosphorylated on Ser residues by GSK-3beta, and that chemical inhibition of GSK-3beta and/or global Caspases increases AAH protein in both control- and ethanol-exposed cells. Ethanol-impaired neuronal migration in FASD is associated with reduced AAH expression. Because ethanol increases the activities of both GSK-3beta and Caspases, the inhibitory effect of ethanol on neuronal migration could be mediated by increased GSK-3beta phosphorylation and Caspase degradation of AAH protein.
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PMID:Ethanol inhibition of aspartyl-asparaginyl-beta-hydroxylase in fetal alcohol spectrum disorder: potential link to the impairments in central nervous system neuronal migration. 1939 62

It has long been known that heavy alcohol consumption leads to neuropathology and neuronal death. While the response of neurons to an ethanol insult is strongly influenced by genetic background, the underlying mechanisms are poorly understood. Here, we show that even a single intoxicating exposure to ethanol causes non-cell-autonomous apoptotic death specifically of Drosophila olfactory neurons, which is accompanied by a loss of a behavioral response to the smell of ethanol and a blackening of the third antennal segment. The Drosophila homolog of glycogen synthase kinase-3 (GSK-3)beta, Shaggy, is required for ethanol-induced apoptosis. Consistent with this requirement, the GSK-3beta inhibitor lithium protects against the neurotoxic effects of ethanol, indicating the possibility for pharmacological intervention in cases of alcohol-induced neurodegeneration. Ethanol-induced death of olfactory neurons requires both their neural activity and functional NMDA receptors. This system will allow the investigation of the genetic and molecular basis of ethanol-induced apoptosis in general and provide an understanding of the molecular role of GSK-3beta in programmed cell death.
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PMID:Glycogen synthase kinase-3/Shaggy mediates ethanol-induced excitotoxic cell death of Drosophila olfactory neurons. 1992 38

Previous studies indicated that ethanol-induced neurodegeneration in postnatal day 7 (P7) mice, widely used as a model for the fetal alcohol spectrum disorders, was accompanied by glycogen synthase kinase-3beta (GSK-3beta) and caspase-3 activation. Presently, we examined whether tau, a microtubule associated protein, is modified by GSK-3beta and caspase-3 in ethanol-treated P7 mouse forebrains. We found that ethanol increased phosphorylated tau recognized by the paired helical filament (PHF)-1 antibody and by the antibody against tau phosphorylated at Ser199. Ethanol also generated tau fragments recognized by an antibody against caspase-cleaved tau (C-tau). C-tau was localized in neurons bearing activated caspase-3 and fragmented nuclei. Over time, cell debris and degenerated projections containing C-tau appeared to be engulfed by activated microglia. A caspase-3 inhibitor partially blocked C-tau formation. Lithium, a GSK-3beta inhibitor, blocked ethanol-induced caspase-3 activation, phosphorylated tau elevation, C-tau formation, and microglial activation. These results indicate that tau is phosphorylated by GSK-3beta and cleaved by caspase-3 during ethanol-induced neurodegeneration in the developing brain.
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PMID:Tau phosphorylation and cleavage in ethanol-induced neurodegeneration in the developing mouse brain. 2004 27

Alcohol consumption leads to myocardial contractile dysfunction possibly due to the toxicity of ethanol and its major metabolite acetaldehyde. This study was designed to examine the influence of mitochondrial aldehyde dehydrogenase-2 (ALDH2) knockout (KO) on acute ethanol exposure-induced cardiomyocyte dysfunction. Wild-type (WT) and ALDH2 KO mice were subjected to acute ethanol (3g/kg, i.p.) challenge and cardiomyocyte contractile function was assessed 24h later using an IonOptix edge detection system. Western blot analysis was performed to evaluate ALDH2, protein phosphatase 2A (PP2A), phosphorylation of Akt, and glycogen synthase kinase-3beta (GSK-3beta). ALDH2 KO accentuated ethanol-induced elevation in cardiac acetaldehyde levels. Ethanol exposure depressed cardiomyocyte contractile function including decreased cell shortening amplitude and maximal velocity of shortening/relengthening as well as prolonged relengthening duration and a greater decline in peak shortening in response to increasing stimulus frequency, the effect of which was significantly exaggerated by ALDH2 KO. ALDH2 KO also unmasked an ethanol-induced prolongation of shortening duration. In addition, short-term in vitro incubation of ethanol-induced cardiomyocyte mechanical defects was exacerbated by the ALDH inhibitor cyanamide. Ethanol treatment dampened phosphorylation of Akt and GSK-3beta associated with upregulated PP2A, which was accentuated by ALDH2 KO. ALDH2 KO aggravated ethanol-induced decrease in mitochondrial membrane potential. These results suggested that ALDH2 deficiency led to worsened ethanol-induced cardiomyocyte function, possibly due to upregulated expression of protein phosphatase, depressed Akt activation, and subsequently impaired mitochondrial function. These findings depict a critical role of ALDH2 in the pathogenesis of alcoholic cardiomyopathy.
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PMID:Aldehyde dehydrogenase 2 knockout accentuates ethanol-induced cardiac depression: role of protein phosphatases. 2036 83

In chronic alcoholism, brain shrinkage and cognitive defects because of neuronal death are well established, although the sequence of molecular events has not been fully explored yet. We explored the role of microRNAs (miRNAs) in ethanol-induced apoptosis of neuronal cells. Ethanol-sensitive miRNAs in SH-SY5Y, a human neuroblastoma cell line, were identified using real-time PCR-based TaqMan low-density arrays. Long-term exposure to ethanol (0.5% v/v for 72 h) produced a maximum increase in expression of miR-497 (474-fold) and miR-302b (322-fold). Similar to SH-SY5Y, long-term exposure to ethanol induced miR-497 and miR-302b in IMR-32, another human neuroblastoma cell line. Using in silico approaches, BCL2 and cyclin D2 (CCND2) were identified as probable target genes of these miRNAs. Cotransfection studies with 3'-UTR of these genes and miRNA mimics have demonstrated that BCL2 is a direct target of miR-497 and that CCND2 is regulated negatively by either miR-302b or miR-497. Overexpression of either miR-497 or miR-302b reduced expression of their identified target genes and increased caspase 3-mediated apoptosis of SH-SY5Y cells. However, overexpression of only miR-497 increased reactive oxygen species formation, disrupted mitochondrial membrane potential, and induced cytochrome c release (mitochondria-related events of apoptosis). Moreover, ethanol induced changes in miRNAs, and their target genes were substantially prevented by pre-exposure to GSK-3B inhibitors. In conclusion, our studies have shown that ethanol-induced neuronal apoptosis follows both the mitochondria-mediated (miR-497- and BCL2-mediated) and non-mitochondria-mediated (miR-302b- and CCND2-mediated) pathway.
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PMID:miR-497 and miR-302b regulate ethanol-induced neuronal cell death through BCL2 protein and cyclin D2. 2187 50


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