Transcriptional Regulation of the Astrocytic Excitatory Amino Acid Transporter 1 (EAAT1) via NF-κB and Yin Yang 1 (YY1)
| Autor: | Keisha Smith, Michael Aschner, Clifford Kim, Eun Sook Lee, Deok Soo Son, Pratap Karki |
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| Rok vydání: | 2015 |
| Předmět: |
Transcription
Genetic Biology Response Elements Biochemistry Histone Deacetylases Epigenesis Genetic Rats Sprague-Dawley medicine Transcriptional regulation Glutamate aspartate transporter Animals Molecular Biology Transcription factor Cells Cultured YY1 Transcription Factor Manganese Messenger RNA Gene knockdown YY1 NF-kappa B Glutamate receptor Molecular Bases of Disease Cell Biology Molecular biology Rats Excitatory Amino Acid Transporter 1 Histone Deacetylase Inhibitors medicine.anatomical_structure Astrocytes biology.protein Astrocyte |
| Zdroj: | Journal of Biological Chemistry. 290:23725-23737 |
| ISSN: | 0021-9258 |
| Popis: | Astrocytic glutamate transporter excitatory amino acid transporter (EAAT) 1, also known as glutamate aspartate transporter (GLAST) in rodents, is one of two glial glutamate transporters that are responsible for removing excess glutamate from synaptic clefts to prevent excitotoxic neuronal death. Despite its important role in neurophysiological functions, the molecular mechanisms of EAAT1 regulation at the transcriptional level remain to be established. Here, we report that NF-κB is a main positive transcription factor for EAAT1, supported by the following: 1) EAAT1 contains two consensus sites for NF-κB, 2) mutation of NF-κB binding sites decreased EAAT1 promoter activity, and 3) activation of NF-κB increased, whereas inhibition of NF-κB decreased EAAT1 promoter activity and mRNA/protein levels. EGF increased EAAT1 mRNA/protein levels and glutamate uptake via NF-κB. The transcription factor yin yang 1 (YY1) plays a role as a critical negative regulator of EAAT1, supported by the following: 1) the EAAT1 promoter contains multiple consensus sites for YY1, 2) overexpression of YY1 decreased EAAT1 promoter activity and mRNA/protein levels, and 3) knockdown of YY1 increased EAAT1 promoter activity and mRNA/protein levels. Manganese decreased EAAT1 expression via YY1. Epigenetic modifiers histone deacetylases (HDACs) served as co-repressors of YY1 to further decrease EAAT1 promoter activity, whereas inhibition of HDACs reversed manganese-induced decrease of EAAT1 expression. Taken together, our findings suggest that NF-κB is a critical positive regulator of EAAT1, mediating the stimulatory effects of EGF, whereas YY1 is a negative regulator of EAAT1 with HDACs as co-repressors, mediating the inhibitory effects of manganese on EAAT1 regulation. |
| Databáze: | OpenAIRE |
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