Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression.
Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression.
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发表时间：
2005
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通讯作者：
R. Sitcheran;P. Gupta;P. Fisher;A. Baldwin
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作者：
R. Sitcheran;P. Gupta;P. Fisher;A. Baldwin
谷氨酸转运蛋白基因EAAT2/GLT-1受表皮生长因子（EGF）诱导，并受肿瘤坏死因子α (TNFalpha)下调。虽然TNFalpha通常被认为是nf - kappab依赖性基因表达的正调节因子，但其控制转录抑制的能力尚未得到很好的表征。此外，EGF对NF-kappaB的调控尚不清楚。本文中，我们证明了tnfalpha介导的EAAT2表达抑制和egf介导的EAAT2表达激活都需要NF-kappaB。我们发现EGF独立于IkappaB信号激活NF-kappaB。此外，TNFalpha可以消除IKKbeta-和p65介导的EAAT2活化。我们的研究结果表明，NF-kappaB可以内在地激活EAAT2，而TNFalpha通过同样需要NF-kappaB的不同途径介导抑制。一致地，我们发现N-myc与TNFalpha一起被募集到EAAT2启动子上，并且TNFalpha介导的抑制需要N-myc结合位点。此外，N-myc过表达抑制基础和p65诱导的EAAT2激活。我们的数据强调了NF-kappaB活性在不同细胞信号下调节基因表达的显著特异性，并对谷氨酸稳态和神经退行性疾病有影响。
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.