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Originally published In Press as doi:10.1074/jbc.M010587200 on January 9, 2001

J. Biol. Chem., Vol. 276, Issue 14, 10817-10823, April 6, 2001
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Transcriptional Regulation of the Mouse Uncoupling Protein-2 Gene
DOUBLE E-BOX MOTIF IS REQUIRED FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-gamma -DEPENDENT ACTIVATION*

Alexander V. MedvedevDagger , Sheridan K. SneddenDagger §, Serge Raimbault||, Daniel Ricquier||, and Sheila CollinsDagger §**

From the Departments of Dagger  Psychiatry and Behavioral Sciences and § Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 and || Centre de Recherche sur l'Endocrinologie Moléculaire et le Developpement, Centre National de la Recherche Scientifique, UPR 9078, Meudon, 92190 France

Uncoupling protein-2 (UCP2) is present in many tissues with relevance to fuel metabolism, and its expression is increased in fat and muscle in response to elevated circulating free fatty acids resulting from fasting and high fat feeding. We proposed a role for peroxisome proliferator-activated receptor-gamma (PPARgamma ) as a mediator of these physiological changes in UCP2, because thiazolidinediones also increase expression of UCP2 in these cell types (1). To determine the molecular basis for this regulation, we isolated the 7.3-kilobase promoter region of the mouse UCP2 gene. The -7.3-kilobase/+12-base pair fragment activates transcription of a reporter gene by 50-100-fold. Deletion and point mutation analysis, coupled with gel shift assays, indicate the presence of a 43-base pair enhancer (-86/-44) that is responsible for the majority of both basal and PPARgamma -dependent transcriptional activity. The distal (-86/-76) part of the enhancer specifically binds Sp1, Sp2, and Sp3 and is indistinguishable from a consensus Sp1 element in competition experiments. Point mutation in this sequence reduces basal activity by 75%. A second region (-74/-66) is identical to the sterol response element consensus and specifically binds ADD1/SREBP1. However, deletion of this sequence does not affect basal transcriptional activity or the response to PPARgamma . The proximal portion of the enhancer contains a direct repeat of two E-Box motifs, which contributes most strongly to basal and PPARgamma -dependent transcription of the UCP2 promoter. Deletion of this region results in a 10-20-fold reduction of transcriptional activity and complete loss of PPARgamma responsiveness. Point mutations in either E-Box, but not in the spacer region between them, eliminate the stimulatory response to PPARgamma . However, gel shift assays show that PPARgamma does not bind to this region. Taken together, these data indicate that PPARgamma activates the UCP2 gene indirectly by altering the activity or expression of other transcription factors that bind to the UCP2 promoter.

* This work was supported in part by National Institutes of Health Grants R01-DK54024 (to S. C.) and F31-DK09812 (to S. K. S. and S. C.), Center National de la Recherche Scientifique (to D. R.), Human Frontier Science Program RG 0307 (to D. R.), Institut de Recherche Servier (to D. R.), and Institut National de la Santé et de la Recherche Médicale Grant 4P007E (to D. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF115319

Supported by National Institutes of Health Predoctoral Fellowship F31-DK09812.

** To whom correspondence should be addressed: Duke University Medical Center, Box 3557, Durham, NC 27710. Tel.: 919-684-8991; Fax: 919-684-3071; E-mail: colli008@mc.duke.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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