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Induction of c-Myc expression suppresses insulin gene transcription by inhibiting NeuroD/BETA2-mediated transcriptional activation.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2002 Apr 12; Vol. 277 (15), pp. 12998-3006. Date of Electronic Publication: 2002 Jan 17. - Publication Year :
- 2002
-
Abstract
- Insulin biosynthesis and secretion are critical for pancreatic beta-cell function, but both are impaired under diabetic conditions. We have found that hyperglycemia induces the expression of the basic helix-loop-helix transcription factor c-Myc in islets in several different diabetic models. To examine the possible implication of c-Myc in beta-cell dysfunction, c-Myc was overexpressed in isolated rat islets using adenovirus. Adenovirus-mediated c-Myc overexpression suppressed both insulin gene transcription and glucose-stimulated insulin secretion. Insulin protein content, determined by immunostaining, was markedly decreased in c-Myc-overexpressing cells. In gel-shift assays c-Myc bound to the E-box in the insulin gene promoter region. Furthermore, in betaTC1, MIN6, and HIT-T15 cells and primary rat islets, wild type insulin gene promoter activity was dramatically decreased by c-Myc overexpression, whereas the activity of an E-box mutated insulin promoter was not affected. In HeLa and HepG2 cells c-Myc exerted a suppressive effect on the insulin promoter activity only in the presence of NeuroD/BETA2 but not PDX-1. Both c-Myc and NeuroD can bind the E-box element in the insulin promoter, but unlike NeuroD, the c-Myc transactivation domain lacked the ability to activate insulin gene expression. Additionally p300, a co-activator of NeuroD, did not function as a co-activator of c-Myc. In conclusion, increased expression of c-Myc in beta-cells suppresses the insulin gene transcription by inhibiting NeuroD-mediated transcriptional activation. This mechanism may explain some of the beta-cell dysfunction found in diabetes.
- Subjects :
- Adenoviridae genetics
Animals
Base Sequence
Basic Helix-Loop-Helix Transcription Factors
DNA Primers
HeLa Cells
Humans
Insulin biosynthesis
Insulin metabolism
Insulin Secretion
Islets of Langerhans metabolism
Male
Promoter Regions, Genetic
Rats
Rats, Sprague-Dawley
DNA-Binding Proteins physiology
Insulin genetics
Proto-Oncogene Proteins c-myc physiology
Trans-Activators physiology
Transcription Factors
Transcriptional Activation physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 277
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11799123
- Full Text :
- https://doi.org/10.1074/jbc.M111148200