Positive and negative regulation of EAAT2 by NF-κB: a role for N-myc in TNFα-controlled repression

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Abstract
The glutamate transporter gene, EAAT2/GLT‐1, is induced by epidermal growth factor (EGF) and downregulated by tumor necrosis factor α (TNFα). While TNFα is generally recognized as a positive regulator of NF‐κB‐dependent gene expression, its ability to control transcriptional repression is not well characterized. Additionally, the regulation of NF‐κB by EGF is poorly understood. Herein, we demonstrate that both TNFα‐mediated repression and EGF‐mediated activation of EAAT2 expression require NF‐κB. We show that EGF activates NF‐κB independently of signaling to IκB. Furthermore, TNFα can abrogate IKKβ‐ and p65‐mediated activation of EAAT2. Our results suggest that NF‐κB can intrinsically activate EAAT2 and that TNFα mediates repression through a distinct pathway also requiring NF‐κB. Consistently, we find that N‐myc is recruited to the EAAT2 promoter with TNFα and that N‐myc‐binding sites are required for TNFα‐mediated repression. Moreover, N‐myc overexpression inhibits both basal and p65‐induced activation of EAAT2. Our data highlight the remarkable specificity of NF‐κB activity to regulate gene expression in response to diverse cellular signals and have implications for glutamate homeostasis and neurodegenerative disease.
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