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J. Biol. Chem., Vol. 279, Issue 16, 15908-15915, April 16, 2004

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Upstream Stimulatory Factor (USF) Proteins Induce Human TGF-1 Gene Activation via the Glucose-response Element–1013/–1002 in Mesangial Cells

UP-REGULATION OF USF ACTIVITY BY THE HEXOSAMINE BIOSYNTHETIC PATHWAY^*

Cora Weigert, Katrin Brodbeck, Michèle Sawadogo¶, Hans U. Häring, and Erwin D. Schleicher||

From the Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, University of Tübingen, D-72076 Tübingen, Germany and the ^¶Department of Molecular Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The hyperglycemia-enhanced flux through the hexosamine biosynthetic pathway (HBP) has been implicated in the up-regulated gene expression of transforming growth factor-1 (TGF-1) in mesangial cells, thus leading to mesangial matrix expansion and diabetic glomerulosclerosis. Since the –1013 to –1002 region of the TGF-1 promoter shows high homology to glucose-response elements (GlRE) formerly described in genes involved in glucose metabolism, we studied the function of the GlRE in the high glucose-induced TGF-1 gene activation in mesangial cells. We found that high glucose concentrations enhanced the nuclear amount of upstream stimulatory factors (USF) and their binding to this sequence. Fusion of the GlRE to the thymidine kinase promoter resulted in glucose responsiveness of this promoter construct. Overexpression of either USF-1 or USF-2 increased TGF-1 promoter activity 2-fold, which was prevented by mutation or deletion of the GlRE. The high glucose-induced activation of the GlRE is mediated by the HBP; increased flux through the HBP induced by high glucose concentrations, by glutamine, or by overexpression of the rate-limiting enzyme glutamine:fructose-6-phosphate aminotransferase (GFAT) particularly activated USF-2 expression. GFAT-overexpressing cells showed higher USF binding activity to the GlRE and enhanced promoter activation via the GlRE. Increasing O-GlcNAc modification of proteins by streptozotocin, thereby mimicking HBP activation, also resulted in increased mRNA and nuclear protein levels of USF-2, leading to enhanced DNA binding activity to the GlRE. USF proteins themselves were not found to be O-GlcNAc-modified. Thus, we have provided evidence for a new molecular mechanism linking high glucose-enhanced HBP activity with increased nuclear USF protein levels and DNA binding activity and with up-regulated TGF-1 promoter activity.

Received for publication, December 10, 2003 , and in revised form, January 28, 2004.

^* The work was supported by Grant Schl 239-7 from the Deutsche Forschungsgemeinschaft (to E. S.). 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.

Present address: INSERM Unit 145, Faculty of Medicine, Nice, France.

^|| To whom correspondence should be addressed: Dept. of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, University of Tübingen, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany. Tel.: 49-7071-29-87599; Fax: 49-7071-29-5974; E-mail: enschlei{at}med.uni-tuebingen.de.

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