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 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.
Shinozuka
Y
Y
Department of Biology, Faculty of Science, Ochanomizu University, 2-1-1, Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
Okada
M
M
Oki
T
T
Sagane
K
K
Mizui
Y
Y
Tanaka
I
I
Katayama
K
K
Murakami-Murofushi
K
K
D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006854:Hydrocortisone / Q000494:pharmacology; D007328:Insulin / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D018398:Homeodomain Proteins; D007328:Insulin; D012333:RNA, Messenger; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D003907:Dexamethasone; D006854:Hydrocortisone