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1 Biochemistry and Molecular Biology, LSU Health Sciences Center, New Orleans, New Orleans, Louisiana, United States; Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, United States
2 Biochemistry and Molecular Biology, LSU Health Sciences Center, New Orleans, New Orleans, Louisiana, United States; Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
3 Biochemistry and Molecular Biology, LSU Health Sciences Center, New Orleans, New Orleans, Louisiana, United States
4 Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States; Biochemistry and Molecular Biology, LSU Health Sciences Center, New Orleans, New Orleans, Louisiana, United States
5 Biochemistry and Molecular Biology, LSU Health Sciences Center, New Orleans, New Orleans, Louisiana, United States; PhosphoSolutions, Aurora, Colorado, United States
* To whom correspondence should be addressed. E-mail: scottd{at}dom.pitt.edu.
Increased glucose flux generates metabolic signals that control transcriptional programs through poorly understood mechanisms. Previously, we demonstrated a necessity in hepatocytes for c-Myc in the regulation of a prototypical glucose-responsive gene, L-type pyruvate kinase (L-PK) (Collier, et al., (2003) J. Biol. Chem. 278, 6588-6595). Pancreatic beta cells have many features in common with hepatocytes with respect to glucose-regulated gene expression, and in the present study we determined if c-Myc was required for the L-PK glucose response in insulin secreting INS-1-derived 832/13 cells. Glucose increased c-Myc abundance and association with its heterodimer partner Max. Manipulations that prevented the formation of a functional c-Myc/Max heterodimer reduced the expression of the L-PK gene. In addition, glucose augmented the binding of ChREBP, c-Myc, and Max to the promoter of the L-PK gene in situ. The transactivation of ChREBP, but not of c-Myc, was dependent on high glucose concentrations in the contexts of either the L-PK promoter or a heterologous promoter. The glucose-mediated transactivation of ChREBP was independent of mutations that alter phosphorylation sites thought to regulate the cellular location of ChREBP. We conclude that maximal glucose-induced expression of the L-PK gene in INS-1-derived 832/13 cells involves increased c-Myc abundance, recruitment of c-Myc, Max, and ChREBP to the promoter, and a glucose-stimulated increase in ChREBP transactivation.
This article has been cited by other articles:
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  S. J. Burke, J. J. Collier, and D. K. Scott cAMP opposes the glucose-mediated induction of the L-PK gene by preventing the recruitment of a complex containing ChREBP, HNF4{alpha}, and CBP FASEB J, September 1, 2009; 23(9): 2855 - 2865. [Abstract] [Full Text] [PDF]
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