Altered Expression of HES-1, BETA2/NeuroD, and PDX-1 Is Involved in Impaired Insulin Synthesis Induced by Glucocorticoids in HIT-T15 Cells

Expression of the insulin gene is highly specific to pancreatic beta cells and is upregulated mainly by PDX-1 and BETA2/NeuroD depending on the extracellular glucose concentration. However, its downregulation has not been well studied. Reporter gene analyses using pancreatic HIT-T15 cells revealed t...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2001-09, Vol.287 (1), p.229-235
Main Authors: Shinozuka, Yoriko, Okada, Masayuki, Oki, Tohru, Sagane, Koji, Mizui, Yoshiharu, Tanaka, Isao, Katayama, Kouichi, Murakami-Murofushi, Kimiko
Format: Article
Language:English
Subjects:
Animals
BETA2 protein
BETA2/NeuroD
Cells, Cultured
Cricetinae
dexamethasone
Dexamethasone - pharmacology
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
glucocorticoids
Glucocorticoids - pharmacology
HES-1
HES-1 protein
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Hydrocortisone - pharmacology
insulin
Insulin - biosynthesis
Islets of Langerhans - drug effects
Islets of Langerhans - metabolism
NeuroD protein
pancreatic beta cells
PDX-1
PDX-1 protein
RNA, Messenger - metabolism
Trans-Activators - genetics
Trans-Activators - metabolism
transcription factor
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Summary:Expression of the insulin gene is highly specific to pancreatic beta cells and is upregulated mainly by PDX-1 and BETA2/NeuroD depending on the extracellular glucose concentration. However, its downregulation has not been well studied. Reporter gene analyses using pancreatic HIT-T15 cells revealed that the glucose-dependent insulin promoter activity was blocked by glucocorticoids, dexamethasone (DEX) and hydrocortisone, in a dose-dependent manner. After the addition of DEX (20 nM) to HIT-T15 cells, a decrease of insulin mRNA was observed at 12–24 h, followed by a decline of insulin protein at 48 h. Expressions of PDX-1 and BETA2/NeuroD decreased within 2 h. HES-1, a potent negative regulator of bHLH-type transcription factors, was found to be expressed in HIT-T15 cells, and its expression was increased 6 h after the addition of DEX. Overexpression of HES-1 suppressed the insulin promoter activity in a dose-dependent manner. These results suggest that glucocorticoids impair insulin synthesis in HIT-T15 cells by decreasing PDX-1 and BETA2/NeuroD and that enhancement of HES-1 expression is involved in this regulation.
ISSN:0006-291X
1090-2104
DOI:10.1006/bbrc.2001.5573