Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression.

The glutamate transporter gene, EAAT2/GLT-1, is induced by epidermal growth factor (EGF) and downregulated by tumor necrosis factor alpha (TNFalpha). While TNFalpha is generally recognized as a positive regulator of NF-kappaB-dependent gene expression, its ability to control transcriptional repression is not well characterized. Additionally, the regulation of NF-kappaB by EGF ...
is poorly understood. Herein, we demonstrate that both TNFalpha-mediated repression and EGF-mediated activation of EAAT2 expression require NF-kappaB. We show that EGF activates NF-kappaB independently of signaling to IkappaB. Furthermore, TNFalpha can abrogate IKKbeta- and p65-mediated activation of EAAT2. Our results suggest that NF-kappaB can intrinsically activate EAAT2 and that TNFalpha mediates repression through a distinct pathway also requiring NF-kappaB. Consistently, we find that N-myc is recruited to the EAAT2 promoter with TNFalpha and that N-myc-binding sites are required for TNFalpha-mediated repression. Moreover, N-myc overexpression inhibits both basal and p65-induced activation of EAAT2. Our data highlight the remarkable specificity of NF-kappaB activity to regulate gene expression in response to diverse cellular signals and have implications for glutamate homeostasis and neurodegenerative disease.
Mesh Terms:
Amino Acid Transport System X-AG, Base Sequence, Cell Line, DNA, Epidermal Growth Factor, Gene Expression Regulation, Glutamate Plasma Membrane Transport Proteins, Humans, Models, Biological, Mutagenesis, Site-Directed, NF-kappa B, Promoter Regions, Genetic, Proto-Oncogene Proteins c-myc, Recombinant Proteins, Signal Transduction, Symporters, Transfection, Tumor Necrosis Factor-alpha
EMBO J.
Date: Feb. 09, 2005
Download Curated Data For This Publication
213004
Switch View:
  • Interactions 2