This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kozak, U C Articles by Kozak, L P Search for Related Content PubMed PubMed Citation Articles by Kozak, U C Articles by Kozak, L P

An upstream enhancer regulating brown-fat-specific expression of the mitochondrial uncoupling protein gene.

Jackson Laboratory, Bar Harbor, Maine 04609.

ABSTRACT

Previous studies on the regulation of a Ucp minigene in transgenic mice demonstrated that the sequences necessary for brown-fat-specific expression and inducibility by norepinephrine were located in the 5' flanking region between 1 and 2.8 kb from the transcriptional start site. We have investigated this region in more detail in cultured mouse brown adipocyte tumor cells. Deletion analysis of two types of chloramphenicol acetyltransferase reporter gene constructs under control of either the Ucp promoter or a heterologous herpes simplex virus-tk promoter defined an enhancer in a 220-bp HindIII-XbaI fragment which was essential for both brown fat specificity and norepinephrine inducibility. Site-directed mutagenesis of the reporter gene constructs established that independent mutations to a cyclic AMP-responsive element (CRE-2) or one of two TTCC motifs (BRE [brown fat regulatory element]), all within 17 bp, eliminated transient expression. Competitive DNA mobility shift assays with probes of the CRE and BRE motifs indicate that nuclear proteins interact with these motifs in a cooperative, synergistic manner. While these CRE-BRE probes do not show changes in binding which is dependent on norepinephrine treatment, a probe containing a third TTCC motif located 130 bp downstream of BRE-1 does show this dependency. The results indicate that a complex interaction of the CRE and BRE motifs, which cannot be functionally separated, control Ucp expression.

This article has been cited by other articles:

• Kumar, N., Liu, D., Wang, H., Robidoux, J., Collins, S. (2008). Orphan Nuclear Receptor NOR-1 Enhances 3',5'-Cyclic Adenosine 5'-Monophosphate-Dependent Uncoupling Protein-1 Gene Transcription. Mol. Endocrinol. 22: 1057-1064 [Abstract] [Full Text]  
• Wang, H., Zhang, Y., Yehuda-Shnaidman, E., Medvedev, A. V., Kumar, N., Daniel, K. W., Robidoux, J., Czech, M. P., Mangelsdorf, D. J., Collins, S. (2008). Liver X Receptor {alpha} Is a Transcriptional Repressor of the Uncoupling Protein 1 Gene and the Brown Fat Phenotype. Mol. Cell. Biol. 28: 2187-2200 [Abstract] [Full Text]  
• Debevec, D., Christian, M., Morganstein, D., Seth, A., Herzog, B., Parker, M., White, R. (2007). Receptor Interacting Protein 140 Regulates Expression of Uncoupling Protein 1 in Adipocytes through Specific Peroxisome Proliferator Activated Receptor Isoforms and Estrogen-Related Receptor {alpha}. Mol. Endocrinol. 21: 1581-1592 [Abstract] [Full Text]  
• Gray, S. L., Dalla Nora, E., Backlund, E. C., Manieri, M., Virtue, S., Noland, R. C., O'Rahilly, S., Cortright, R. N., Cinti, S., Cannon, B., Vidal-Puig, A. (2006). Decreased Brown Adipocyte Recruitment and Thermogenic Capacity in Mice with Impaired Peroxisome Proliferator-Activated Receptor (P465L PPAR{gamma}) Function. Endocrinology 147: 5708-5714 [Abstract] [Full Text]  
• Silva, J. E. (2006). Thermogenic Mechanisms and Their Hormonal Regulation. Physiol. Rev. 86: 435-464 [Abstract] [Full Text]  
• Christian, M., Kiskinis, E., Debevec, D., Leonardsson, G., White, R., Parker, M. G. (2005). RIP140-Targeted Repression of Gene Expression in Adipocytes. Mol. Cell. Biol. 25: 9383-9391 [Abstract] [Full Text]  
• Xue, B., Coulter, A., Rim, J. S., Koza, R. A., Kozak, L. P. (2005). Transcriptional Synergy and the Regulation of Ucp1 during Brown Adipocyte Induction in White Fat Depots. Mol. Cell. Biol. 25: 8311-8322 [Abstract] [Full Text]  
• Robidoux, J., Cao, W., Quan, H., Daniel, K. W., Moukdar, F., Bai, X., Floering, L. M., Collins, S. (2005). Selective Activation of Mitogen-Activated Protein (MAP) Kinase Kinase 3 and p38{alpha} MAP Kinase Is Essential for Cyclic AMP-Dependent UCP1 Expression in Adipocytes. Mol. Cell. Biol. 25: 5466-5479 [Abstract] [Full Text]  
• Valverde, A. M., Mur, C., Brownlee, M., Benito, M. (2004). Susceptibility to Apoptosis in Insulin-like Growth Factor-I Receptor-deficient Brown Adipocytes. Mol. Biol. Cell 15: 5101-5117 [Abstract] [Full Text]  
• Collins, S., Cao, W., Robidoux, J. (2004). Learning New Tricks from Old Dogs: {beta}-Adrenergic Receptors Teach New Lessons on Firing Up Adipose Tissue Metabolism. Mol. Endocrinol. 18: 2123-2131 [Abstract] [Full Text]  
• Rim, J. S., Xue, B., Gawronska-Kozak, B., Kozak, L. P. (2004). Sequestration of Thermogenic Transcription Factors in the Cytoplasm during Development of Brown Adipose Tissue. J. Biol. Chem. 279: 25916-25926 [Abstract] [Full Text]  
• Cao, W., Daniel, K. W., Robidoux, J., Puigserver, P., Medvedev, A. V., Bai, X., Floering, L. M., Spiegelman, B. M., Collins, S. (2004). p38 Mitogen-Activated Protein Kinase Is the Central Regulator of Cyclic AMP-Dependent Transcription of the Brown Fat Uncoupling Protein 1 Gene. Mol. Cell. Biol. 24: 3057-3067 [Abstract] [Full Text]  
• Golozoubova, V., Gullberg, H., Matthias, A., Cannon, B., Vennstrom, B., Nedergaard, J. (2004). Depressed Thermogenesis but Competent Brown Adipose Tissue Recruitment in Mice Devoid of All Hormone-Binding Thyroid Hormone Receptors. Mol. Endocrinol. 18: 384-401 [Abstract] [Full Text]  
• CANNON, B., NEDERGAARD, J. (2004). Brown Adipose Tissue: Function and Physiological Significance. Physiol. Rev. 84: 277-359 [Abstract] [Full Text]  
• Arribas, M., Valverde, A. M., Benito, M. (2003). Role of IRS-3 in the Insulin Signaling of IRS-1-deficient Brown Adipocytes. J. Biol. Chem. 278: 45189-45199 [Abstract] [Full Text]  
• Tiraby, C., Tavernier, G., Lefort, C., Larrouy, D., Bouillaud, F., Ricquier, D., Langin, D. (2003). Acquirement of Brown Fat Cell Features by Human White Adipocytes. J. Biol. Chem. 278: 33370-33376 [Abstract] [Full Text]  
• Coulter, A. A., Bearden, C. M., Liu, X., Koza, R. A., Kozak, L. P. (2003). Dietary fat interacts with QTLs controlling induction of Pgc-1{alpha} and Ucp1 during conversion of white to brown fat. Physiol. Genomics 14: 139-147 [Abstract] [Full Text]  
• Valverde, A. M., Arribas, M., Mur, C., Navarro, P., Pons, S., Cassard-Doulcier, A.-M., Kahn, C. R., Benito, M. (2003). Insulin-induced Up-regulated Uncoupling Protein-1 Expression Is Mediated by Insulin Receptor Substrate 1 through the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Fetal Brown Adipocytes. J. Biol. Chem. 278: 10221-10231 [Abstract] [Full Text]  
• Puigserver, P., Spiegelman, B. M. (2003). Peroxisome Proliferator-Activated Receptor-{gamma} Coactivator 1{alpha} (PGC-1{alpha}): Transcriptional Coactivator and Metabolic Regulator. Endocr. Rev. 24: 78-90 [Abstract] [Full Text]  
• Cettour-Rose, P., Burger, A. G., Meier, C. A., Visser, T. J., Rohner-Jeanrenaud, F. (2002). Central stimulatory effect of leptin on T3 production is mediated by brown adipose tissue type II deiodinase. Am. J. Physiol. Endocrinol. Metab. 283: E980-E987 [Abstract] [Full Text]  
• Rim, J. S., Kozak, L. P. (2002). Regulatory Motifs for CREB-binding Protein and Nfe2l2 Transcription Factors in the Upstream Enhancer of the Mitochondrial Uncoupling Protein 1 Gene. J. Biol. Chem. 277: 34589-34600 [Abstract] [Full Text]  
• Valet, P., Tavernier, G., Castan-Laurell, I., Saulnier-Blache, J. S., Langin, D. (2002). Understanding adipose tissue development from transgenic animal models. J. Lipid Res. 43: 835-860 [Abstract] [Full Text]  
• Oberkofler, H., Esterbauer, H., Linnemayr, V., Strosberg, A. D., Krempler, F., Patsch, W. (2002). Peroxisome Proliferator-activated Receptor (PPAR) gamma Coactivator-1 Recruitment Regulates PPAR Subtype Specificity. J. Biol. Chem. 277: 16750-16757 [Abstract] [Full Text]  
• Argyropoulos, G., Harper, M.-E. (2002). Molecular Biology of Thermoregulation: Invited Review: Uncoupling proteins and thermoregulation. J. Appl. Physiol. 92: 2187-2198 [Abstract] [Full Text]  
• Collins, S., Cao, W., Daniel, K. W., Dixon, T. M., Medvedev, A. V., Onuma, H., Surwit, R. (2001). Adrenoceptors, Uncoupling Proteins, and Energy Expenditure. Exp. Biol. Med. 226: 982-990 [Abstract] [Full Text]  
• Viengchareun, S., Penfornis, P., Zennaro, M.-C., Lombes, M. (2001). Mineralocorticoid and glucocorticoid receptors inhibit UCP expression and function in brown adipocytes. Am. J. Physiol. Endocrinol. Metab. 280: E640-E649 [Abstract] [Full Text]  
• Hernandez, A., Obregon, M. J. (2000). Triiodothyronine amplifies the adrenergic stimulation of uncoupling protein expression in rat brown adipocytes. Am. J. Physiol. Endocrinol. Metab. 278: E769-E777 [Abstract] [Full Text]  
• Shimura, H., Miyazaki, A., Haraguchi, K., Endo, T., Onaya, T. (1998). Analysis of Differentiation-Induced Expression Mechanisms of Thyrotropin Receptor Gene in Adipocytes. Mol. Endocrinol. 12: 1473-1486 [Abstract] [Full Text]  
• Yubero, P., Barberá, M., Alvarez, R., Viñas, O., Mampel, T., Iglesias, R., Villarroya, F., Giralt, M. (1998). Dominant Negative Regulation by c-Jun of Transcription of the Uncoupling Protein-1 Gene through a Proximal cAMP-Regulatory Element: A Mechanism for Repressing Basal and Norepinephrine-Induced Expression of the Gene before Brown Adipocyte Differentiation. Mol. Endocrinol. 12: 1023-1037 [Abstract] [Full Text]  
• Vega, R. B., Kelly, D. P. (1997). A Role for Estrogen-related Receptor alpha  in the Control of Mitochondrial Fatty Acid beta -Oxidation during Brown Adipocyte Differentiation. J. Biol. Chem. 272: 31693-31699 [Abstract] [Full Text]  
• Rabelo, R., Camirand, A., Silva, J. E. (1997). 3',5'-Cyclic Adenosine Monophosphate-Response Sequences of the Uncoupling Protein Gene Are Sequentially Recruited During Darglitazone-Induced Brown Adipocyte Differentiation. Endocrinology 138: 5325-5332 [Abstract] [Full Text]  
• Soloveva, V., Graves, R. A., Rasenick, M. M., Spiegelman, B. M., Ross, S. R. (1997). Transgenic Mice Overexpressing the {beta}1-Adrenergic Receptor in Adipose Tissue Are Resistant to Obesity. Mol. Endocrinol. 11: 27-38 [Abstract] [Full Text]  
• Shimizu, Y., Tanishita, T., Minokoshi, Y., Shimazu, T. (1997). Activation of Mitogen-Activated Protein Kinase by Norepinephrine in Brown Adipocytes from Rats. Endocrinology 138: 248-253 [Abstract] [Full Text]  
• Larose, M., Cassard-Doulcier, A.-M., Fleury, C., Serra, F., Champigny, O., Bouillaud, F., Ricquier, D. (1996). Essential cis-Acting Elements in Rat Uncoupling Protein Gene Are in an Enhancer Containing a Complex Retinoic Acid Response Domain. J. Biol. Chem. 271: 31533-31542 [Abstract] [Full Text]  
• Tai, T.-A. C., Jennermann, C., Brown, K. K., Oliver, B. B., MacGinnitie, M. A., Wilkison, W. O., Brown, H. R., Lehmann, J. M., Kliewer, S. A., Morris, D. C., Graves, R. A. (1996). Activation of the Nuclear Receptor Peroxisome Proliferator-activated Receptor gamma Promotes Brown Adipocyte Differentiation. J. Biol. Chem. 271: 29909-29914 [Abstract] [Full Text]  
• Alvarez, R., de Andrés, J., Yubero, P., Viñas, O., Mampel, T., Iglesias, R., Giralt, M., Villarroya, F. (1995). A Novel Regulatory Pathway of Brown Fat Thermogenesis. J. Biol. Chem. 270: 5666-5673 [Abstract] [Full Text]  
• del Mar Gonzalez-Barroso, M., Pecqueur, C., Gelly, C., Sanchis, D., Alves-Guerra, M.-C., Bouillaud, F., Ricquier, D., Cassard-Doulcier, A.-M. (2000). Transcriptional Activation of the Human ucp1 Gene in a Rodent Cell Line. SYNERGISM OF RETINOIDS, ISOPROTERENOL, AND THIAZOLIDINEDIONE IS MEDIATED BY A MULTIPARTITE RESPONSE ELEMENT. J. Biol. Chem. 275: 31722-31732 [Abstract] [Full Text]  
• Cao, W., Medvedev, A. V., Daniel, K. W., Collins, S. (2001). beta -Adrenergic Activation of p38 MAP Kinase in Adipocytes. cAMP INDUCTION OF THE UNCOUPLING PROTEIN 1 (UCP1) GENE REQUIRES p38 MAP KINASE. J. Biol. Chem. 276: 27077-27082 [Abstract] [Full Text]  
• Schick, B. P., Petrushina, I., Brodbeck, K. C., Castronuevo, P. (2001). Promoter Regulatory Elements and DNase I-hypersensitive Sites Involved in Serglycin Proteoglycan Gene Expression in Human Erythroleukemia, CHRF 288-11, and HL-60 Cells. J. Biol. Chem. 276: 24726-24735 [Abstract] [Full Text]