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J. Biol. Chem., Vol. 279, Issue 25, 26768-26779, June 18, 2004

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Trans-activators Regulating Neuronal Glucose Transporter Isoform-3 Gene Expression in Mammalian Neurons^*

Augustine Rajakumar, Shanthie Thamotharan¶, Nupur Raychaudhuri¶, Ram K. Menon||, and Sherin U. Devaskar¶**

From the ^¶Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, California 90095-1752, the Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute and University of Pittsburgh, Pittsburgh, Pennsylvania 15213, and ^||Division of Endocrinology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109

The murine facilitative glucose transporter isoform 3 is developmentally regulated and is predominantly expressed in neurons. By employing the primer extension assay, the transcription start site of the murine Glut 3 gene in the brain was localized to -305 bp 5' to the ATG translation start codon. Transient transfection assays in N2A neuroblasts using murine GLUT3-luciferase reporter constructs mapped enhancer activities to two regions located at -203 to -177 and -104 to -29 bp flanking a previously described repressor element (-137 to -130 bp). Dephosphorylated Sp1 and Sp3 proteins from the 1- and 21-day-old mouse brain nuclear extracts bound the repressor elements, whereas both dephosphorylated and phosphorylated cAMP-response element-binding protein (CREB) in N2A, 1- and 21-day-old mouse brain nuclear extracts bound the 5'-enhancer cis-elements (-187 to -180 bp) of the Glut 3 gene, and the Y box protein MSY-1 bound the sense strand of the -83- to -69-bp region. Sp3, CREB, and MSY-1 binding to the GLUT 3 DNA was confirmed by the chromatin immunoprecipitation assay, whereas CREB and MSY-1 interaction was detected by the co-immunoprecipitation assay. Furthermore, small interference RNA targeted at CREB in N2A cells decreased endogenous CREB concentrations, and CREB mediated GLUT 3 transcription. Thus, in the murine brain similar to the N2A cells, phosphorylated CREB and MSY-1 bound the Glut 3 gene trans-activating the expression in neurons, whereas Sp1/Sp3 bound the repressor elements. We speculate that phosphorylated CREB and Sp3 also interacted to bring about GLUT 3 expression in response to development/cell differentiation and neurotransmission.

Received for publication, March 10, 2004

^* This work was supported by National Institutes of Health Grants HD33997, HD25024, and HD41230. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Pediatrics, David Geffen School of Medicine, UCLA, 10833 Le Conte Ave., MDCC B2-375, Los Angeles, CA 90024-1752. Tel.: 310-825-9357; Fax: 310-794-6638.

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