Article
- The EMBO Journal (2005) 24, 510 - 520
- doi:10.1038/sj.emboj.7600555
Published online: 20 January 2005
Subject Categories:
Positive and negative regulation of EAAT2 by NF-
B: a role for N-myc in TNF
-controlled repression
Raquel Sitcheran1, Pankaj Gupta2, Paul B Fisher2,3 and Albert S Baldwin1,4
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA
- Department of Pathology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA
- Departments of Neurosurgery and Urology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA
- Department of Biology, University of North Carolina at Chapel Hill, NC, USA
Correspondence to:
Albert S Baldwin, 22-000 Lineberger Comprehensive Cancer Center, CB#7295, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA. Tel.: +1 919 966 3652; Fax: +1 919 966 0444; E-mail: abaldwin@med.unc.edu or jhall@med.unc.edu
Received 21 June 2004; Accepted 21 December 2004
Abstract
The glutamate transporter gene, EAAT2/GLT-1, is induced by epidermal growth factor (EGF) and downregulated by tumor necrosis factor
(TNF
). While TNF
is generally recognized as a positive regulator of NF-
B-dependent gene expression, its ability to control transcriptional repression is not well characterized. Additionally, the regulation of NF-
B by EGF is poorly understood. Herein, we demonstrate that both TNF
-mediated repression and EGF-mediated activation of EAAT2 expression require NF-
B. We show that EGF activates NF-
B independently of signaling to I
B. Furthermore, TNF
can abrogate IKK
- and p65-mediated activation of EAAT2. Our results suggest that NF-
B can intrinsically activate EAAT2 and that TNF
mediates repression through a distinct pathway also requiring NF-
B. Consistently, we find that N-myc is recruited to the EAAT2 promoter with TNF
and that N-myc-binding sites are required for TNF
-mediated repression. Moreover, N-myc overexpression inhibits both basal and p65-induced activation of EAAT2. Our data highlight the remarkable specificity of NF-
B activity to regulate gene expression in response to diverse cellular signals and have implications for glutamate homeostasis and neurodegenerative disease.
Keywords:
- EAAT2,
- EGF,
- N-myc,
- NF-
B, - TNF

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