title: cAMP response element-binding protein (CREB) and nuclear factor κB mediate the tamoxifen-induced up-regulation of glutamate transporter 1 (GLT-1) in rat astrocytes.
abstract: Tamoxifen (TX), a selective estrogen receptor modulator, exerts antagonistic effects on breast tissue and is used to treat breast cancer. Recent evidence also suggests that it may act as an agonist in brain tissue. We reported previously that TX enhanced the expression and function of glutamate transporter 1 (GLT-1) in rat astrocytes, an effect that was mediated by TGF-α. To gain further insight into the mechanisms that mediate TX-induced up-regulation of GLT-1 (EAAT2 in humans), we investigated its effect on GLT-1 at the transcriptional level. TX phosphorylated the cAMP response element-binding protein (CREB) and recruited CREB to the GLT-1 promoter consensus site. The effect of TX on astrocytic GLT-1 was attenuated by the inhibition of PKA, the upstream activator of the CREB pathway. In addition, the effect of TX on GLT-1 promoter activity was abolished by the inhibition of the NF-κB pathway. Furthermore, TX recruited the NF-κB subunits p65 and p50 to the NF-κB binding domain of the GLT-1 promoter. Mutation of NF-κB (triple, -583/-282/-251) or CRE (-308) sites on the GLT-1 promoter led to significant repression of the promoter activity, but neither mutant completely abolished the TX-induced GLT-1 promoter activity. Mutation of both the NF-κB (-583/-282/-251) and CRE (-308) sites led to a complete abrogation of the effect of TX on GLT-1 promoter activity. Taken together, our findings establish that TX regulates GLT-1 via the CREB and NF-κB pathways.
authors: From the Department of Physiology, Meharry Medical College, Nashville, Tennessee 37208.
authors: Pratap
authors: P
authors: Karki
authors: Anton
authors: A
authors: Webb
authors: Keisha
authors: K
authors: Smith
authors: Kyuwon
authors: K
authors: Lee
authors: Deok-Soo
authors: DS
authors: Son
authors: Michael
authors: M
authors: Aschner
authors: Eunsook
authors: E
authors: Lee
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D001665:Binding Sites; D002457:Cell Extracts; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002457:Cell Extracts; D017362:Cyclic AMP Response Element-Binding Protein; D027342:Excitatory Amino Acid Transporter 2; C520305:Gper1 protein, rat; D016328:NF-kappa B; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C493395:Slc1a2 protein, rat; D016211:Transforming Growth Factor alpha; D013629:Tamoxifen; D019061:src-Family Kinases
keywords: Astrocytes; CREB; EAAT2; Glutamate; NF-κB; TGF-α); Tamoxifen
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