Trichostatin A Enhances Glutamate Transporter GLT-1 mRNA Levels in C6 Glioma Cells via Neurosteroid-Mediated Cell Differentiation

Itoh, Mari; Hiroi, Takara; Nishibori, Naoyoshi; Sagara, Takefumi; Her, Song; Lee, Mi-Sook; Morita, Kyoji

doi:10.1007/s12031-012-9842-1

Cited by 11 publications

(12 citation statements)

References 31 publications

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“…YY1 recruits epigenetic corepressors to exert its repressive gene regulation (18). Given the role of HDAC inhibitors in upregulation of glutamate transporter gene expression (27), we determined if HDACs play a corepressor role in YY1-induced EAAT2 inhibition. First, we studied the effect of overexpression of HDAC subtype members belonging to classes I and II on EAAT2 promoter activity.…”

Section: Resultsmentioning

confidence: 99%

“…Several studies have shown the neuroprotective effects of HDAC inhibitors in various neurodegenerative disease models (see reference 28 for a review). Moreover, HDAC inhibitors afford neuroprotection by upregulating glutamate transporters (27). Accordingly, we addressed the role of HDACs in EAAT2 regulation and Mn repression of EAAT2.…”

Section: Resultsmentioning

confidence: 99%

“…This is interesting because reduction of EAAT2 expression is observed in both excitotoxic neuronal injury and glioblastoma (24). A classical HDACi, trichostatin A, has been shown to enhance GLT-1 mRNA levels in C6 glioma cells (27). The mitigating effect of Mn-induced EAAT2 repression by HDACi is likely independent of counteracting Mn action because the reversing effect of EAAT2 promoter activity was significantly higher than the basal levels.…”

Section: Fig 10mentioning

confidence: 99%

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Yin Yang 1 Is a Repressor of Glutamate Transporter EAAT2, and It Mediates Manganese-Induced Decrease of EAAT2 Expression in Astrocytes

Karki

Webb

Smith

et al. 2014

Molecular and Cellular Biology

139

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c Impairment of astrocytic glutamate transporter (GLT-1; EAAT2) function is associated with multiple neurodegenerative diseases, including Parkinson's disease (PD) and manganism, the latter being induced by chronic exposure to high levels of manganese (Mn). Mn decreases EAAT2 promoter activity and mRNA and protein levels, but the molecular mechanism of Mn-induced EAAT2 repression at the transcriptional level has yet to be elucidated. We reveal that transcription factor Yin Yang 1 (YY1) is critical in repressing EAAT2 and mediates the effects of negative regulators, such as Mn and tumor necrosis factor alpha (TNF-␣), on EAAT2. YY1 overexpression in astrocytes reduced EAAT2 promoter activity, while YY1 knockdown or mutation of the YY1 consensus site of the EAAT2 promoter increased its promoter activity and attenuated the Mn-induced repression of EAAT2. Mn increased YY1 promoter activity and mRNA and protein levels via NF-B activation. This led to increased YY1 binding to the EAAT2 promoter region. Epigenetically, histone deacetylase (HDAC) classes I and II served as corepressors of YY1, and, accordingly, HDAC inhibitors increased EAAT2 promoter activity and reversed the Mn-induced repression of EAAT2 promoter activity. Taken together, our findings suggest that YY1, with HDACs as corepressors, is a critical negative transcriptional regulator of EAAT2 and mediates Mn-induced EAAT2 repression.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Fig 10mentioning

confidence: 99%

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Yin Yang 1 Is a Repressor of Glutamate Transporter EAAT2, and It Mediates Manganese-Induced Decrease of EAAT2 Expression in Astrocytes

Karki

Webb

Smith

et al. 2014

Molecular and Cellular Biology

139

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“…Histone acetylation modification is characterized by the addition and removal of acetyl moiety from acetyl-coenzyme A to the ε-amino group of lysine residue; this reaction is carried out by two enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs) [71]. Histone deacetylases (HDACs) inhibitors, such as TSA and valproic acid (VPA) increase EAAT2 mRNA and protein levels, indicating the role of acetylation in regulating EAAT2 expression [64, 72, 73]. In addition, CREB-binding protein (CBP), a HAT, has been reported to contribute as a co-repressor of YY1 in the negative regulation of EAAT2 [26].…”

Section: Epigenetic Deregulation In Neurological Disordersmentioning

confidence: 99%

Genetic Dys-regulation of Astrocytic Glutamate Transporter EAAT2 and its Implications in Neurological Disorders and Manganese Toxicity

et al. 2014

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Astrocytic glutamate transporters, the excitatory amino acid transporter (EAAT) 2 and EAAT1 [glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST) in rodents, respectively], are the main transporters for maintaining optimal glutamate levels in the synaptic clefts by taking up more than 90% of glutamate from extracellular space thus preventing excitotoxic neuronal death. Reduced expression and function of these transporters, especially EAAT2, has been reported in numerous neurological disorders, including amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, schizophrenia and epilepsy. The mechanism of down-regulation of EAAT2 in these diseases has yet to be fully established. Genetic as well as transcriptional dys-regulation of these transporters by various modes, such as single nucleotide polymorphisms (SNPs) and epigenetics, resulting in impairment of their functions, might play an important role in the etiology of neurological diseases. Consequently, there has been an extensive effort to identify molecular targets for enhancement of EAAT2 expression as a potential therapeutic approach. Several pharmacological agents increase expression of EAAT2 via NF-κB and CREB at the transcriptional level. However, the negative regulatory mechanisms of EAAT2 have yet to be identified. Recent studies, including those from our laboratory, suggest that the transcriptional factor yin yang 1 (YY1) plays a critical role in the repressive effects of various neurotoxins, such as manganese (Mn), on EAAT2 expression. In this review, we will focus on transcriptional epigenetics, and translational regulation of EAAT2.

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“…Mn-induced oxidative stress may also repress GLT-1 promoter activity because oxidative stress has been reported to be a causal factor for impairment of GLT-1 in experimental and clinical studies. [122][123][124][125] YY1 also interacts with an epigenetic modifier HDAC1, which is enhanced by Mn, 65 indicating that HDACs serve as co-repressors of YY1 and inhibition of HDACs with pharmacological inhibitors increases GLT-1 promoter activity 126,127 and attenuates Mn-reduced GLT-1 promoter activity. 65 …”

Section: Yy1 Is a Negative Regulator Of The Glt-1 Promotermentioning

confidence: 99%

Mechanism of Manganese-Induced Impairment of Astrocytic Glutamate Transporters

Karki¹,

Smith²,

Aschner³

et al. 2014

Manganese in Health and Disease

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Manganese (Mn) is an essential trace element, playing a vital role in numerous biochemical and cellular reactions; however, chronic exposure to high Mn levels from environmental and occupational sources causes a neurological disorder with shared features of Parkinson's disease (PD), referred to as manganism. Despite well-established pathological signs, the molecular mechanism(s) by which Mn induces these neurological disorders still remain to be established. In addition to oxidative stress and impairment of mitochondria, Mn dysregulates astrocytic glutamate transporters (GLAST [glutamate aspartate transporter] and GLT-1 [glutamate transporter 1]) by decreasing their promoter activity, mRNA, and protein levels as well as astrocytic glutamate uptake. The Mn-induced impairment in glutamate transporters is directly associated with excitotoxic neuronal death because the astrocytic glutamate transporters, GLAST and GLT-1, are mainly responsible for maintaining optimal glutamate levels in the synaptic clefts, thereby preventing glutamate-induced neuronal excitotoxicity. It is widely recognized that reduced expression and function of astrocytic glutamate transporters, in particular GLT-1, are associated with various neurodegenerative diseases, including PD and amyotrophic lateral sclerosis (ALS). Therefore, Mn-induced impairment of astrocytic glutamate transporters might be a critical mechanism for Mn neurotoxicity. Our latest studies have uncovered a novel mechanism of Mn-induced repression of GLT-1 at the transcriptional level. It appears that the transcription factor yin yang 1 (YY1) plays a critical role in Mn-induced repression of GLT-1 promoter activity and expression. Herein, we will discuss the cellular and molecular mechanisms by which Mn induces neurotoxicity, such as oxidative stress, mitochondrial impairment, inflammation, and dysregulation of glutamate transporters.

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Trichostatin A Enhances Glutamate Transporter GLT-1 mRNA Levels in C6 Glioma Cells via Neurosteroid-Mediated Cell Differentiation

Cited by 11 publications

References 31 publications

Yin Yang 1 Is a Repressor of Glutamate Transporter EAAT2, and It Mediates Manganese-Induced Decrease of EAAT2 Expression in Astrocytes

Yin Yang 1 Is a Repressor of Glutamate Transporter EAAT2, and It Mediates Manganese-Induced Decrease of EAAT2 Expression in Astrocytes

Genetic Dys-regulation of Astrocytic Glutamate Transporter EAAT2 and its Implications in Neurological Disorders and Manganese Toxicity

Mechanism of Manganese-Induced Impairment of Astrocytic Glutamate Transporters

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