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

Raquel Sitcheran, Pankaj Gupta, Paul B. Fisher, Albert S. Baldwin

Research output: Contribution to journalArticlepeer-review

152 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)510-520
Number of pages11
JournalEMBO Journal
Volume24
Issue number3
DOIs
StatePublished - Feb 9 2005

Keywords

  • EAAT2
  • EGF
  • N-myc
  • NF-κb
  • TNFα

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