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1 Biochemistry and Molecular Biology, LSU Health Sciences Center, New Orleans, New Orleans, Louisiana, United States
2 Biology, Xavier University, United States; Matematics and Natural Sciences, Collin Community College, Plano, Texas, United States
3 Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina, United States; Pharmacology and Cancer Biology, United States; Medicine, United States; Biochemistry, United States
4 Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States
* To whom correspondence should be addressed. E-mail: dscott3{at}lsuhsc.edu.
Glucose homeostasis requires the proper expression and regulation of the catalytic subunit of glucose-6-phosphatase (G6Pase), which hydrolyzes glucose-6-phosphate to glucose in glucose-producing tissues. Glucose induces the expression of G6Pase at the transcriptional and post-transcriptional levels by unknown mechanisms. To better understand this metabolic regulation, we mapped the cis-regulatory elements conferring glucose responsiveness to the rat G6Pase gene promoter in glucose-responsive cell lines. The full-length (-4078/+64) promoter conferred a moderate glucose response to a reporter construct in HL1C rat hepatoma cells, which was dependent on co-expression of glucokinase. The same construct provided a robust glucose response in 832/13 INS-1 rat insulinoma cells, which are not glucogenic. Glucose also strongly increased endogenous G6Pase mRNA levels in 832/13 cells and in rat pancreatic islets, though the induced levels from islets were still markedly lower than in untreated primary hepatocytes. A distal promoter region was glucose-responsive in 832/13 cells and contained a carbohydrate response element (ChoRE) with two E-boxes separated by five base pairs. Carbohydrate Response Element Binding Protein (ChREBP) bound this region in a glucose-dependent manner in situ. A second, proximal promoter region was glucose-responsive in both 832/13 and HL1C cells, with a Hepatocyte Nuclear Factor 1 binding site and two cAMP-response elements required for glucose responsiveness. Expression of dominant negative versions of both CREB and C/EBP blocked the glucose response of the proximal region in a dose-dependent manner. We conclude that multiple, distinct cis-regulatory promoter elements are involved in the glucose response of the rat G6Pase gene.
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