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This version published online on January 13, 2005
Molecular Endocrinology, doi:10.1210/me.2003-0493
A more recent version of this article appeared on May 1, 2005
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Submitted on December 23, 2003
Accepted on January 4, 2005

Elevated glucose attenuates human insulin gene promoter activity in INS-1 pancreatic {beta} cells via reduced nuclear factor binding to the A5/core and Z element

Maria F. Pino, Diana Z. Ye, Katrina D. Linning, Christopher D. Green, Barton Wicksteed, Vincent Poitout, and L. Karl Olson*

Department of Physiology, Michigan State University, East Lansing, MI 48824; Department of Pharmacology, Michigan State University, East Lansing, MI 48824; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824; Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122; Department of Medicine, University of Washington, Seattle, WA 98195 ; Department of Physiology, Michigan State University, East Lansing, MI 48824; Department of Pharmacology, Michigan State University, East Lansing, MI 48824; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824; Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122; Department of Medicine, University of Washington, Seattle, WA 98195

* To whom correspondence should be addressed. E-mail: olsonla{at}msu.edu.

Chronic exposure of pancreatic {beta} cells to elevated glucose reduces insulin gene promoter activity and this is associated with diminished binding of two {beta} cell-enriched transcription factors, Pdx-1 and MafA. In this study using INS-1 {beta} cells, over-expression of MafA, but not Pdx-1, was able to restore expression of a human insulin reporter gene (-327 to +30 bp) suppressed by elevated glucose. At issue, however, was that MafA also markedly stimulated an insulin reporter gene (-230 to +30 bp) that was only marginally suppressed by glucose suggesting that glucose-mediated suppression of the insulin promoter involved elements upstream of -230. Using serial truncations and minienhancer constructs of the human insulin promoter, the majority of glucose suppression was localized to regulatory elements between -327 and -261. Nuclear extracts from INS-1 cells exposed to elevated glucose had reduced binding activities to the A5/core (-319 to -307), and to a palindrome (-284 to -267) and an E-box (-273 to -257, E3) contained within the Z element. The A5/core binding complex was determined to contain MafA, Pdx-1, and an A2-like binding factor. Two minienhancer constructs containing the A5/core were suppressed by glucose and strongly activated by MafA. Glucose-mediated suppression of the Z minienhancer was not attenuated by over-expression of MafA or Pdx-1. Site-directed mutation of the A5/core, palindrome, and E3 elements attenuated glucose-mediated suppression. These data indicate that glucose suppression of human insulin promoter activity in INS-1 cells involves reduced binding of MafA to the A5/core. Changes in nuclear factor binding to the Z element, which functions as a strong activator element in primary islets and a negative regulatory element in SV40 or T-antigen transformed {beta} cell-lines, also participate in glucose suppression of insulin promoter activity.
Key words: insulin gene transcription • glucose toxicity • MafA • Pdx-1 • {beta} cells




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