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Papers In Press, published online ahead of print February 2, 2004
Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemie, University of Tuebingen, Tuebingen 72076
Corresponding Author: caweiger{at}med.uni-tuebingen.de
The hyperglycemia-enhanced flux through the hexosamine biosynthetic pathway (HBP) has been implicated in the upregulated gene expression of transforming growth factor-ß1 (TGF-
J. Biol. Chem, 10.1074/jbc.M313524200
Submitted on December 10, 2003
Revised on January 28, 2004
Accepted on February 2, 2004
USF proteins induce human TGF-beta1 gene activation via the glucose response element -1013/-1002 in mesangial cells - upregulation of USF activity by the hexosamine biosynthetic pathway
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) activated particularly 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, resulted also 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.
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