Transforming growth factor beta induction of insulin gene expression is mediated by pancreatic and duodenal homeobox gene-1 in rat insulinoma cells.
Although transforming growth factor-beta (TGF-beta) stimulates pancreatic islet cells to synthesize and secret insulin, the mechanism underlying this effect is not known. To investigate this question, we examined the insulin promoter activity focusing on a transcription factor, pancreatic and duodenal homeobox gene-1 (PDX-1) that binds to the A3 element of the rat insulin promoter. Studies performed using the rat insulinoma cell line, INS-1 showed that TGF-beta stimulation of endogenous insulin mRNA expression correlated with increased activity of a reporter construct containing the insulin promoter. A potential mechanism for this increase arose from, electrophoretic mobility shift assay showing that the nuclear extract from TGF-beta treated cells contained higher levels of A3 binding activity. Western blot analysis confirmed that PDX-1 was increased in the nuclear extract from INS-1 cells treated with TGF-beta. As expected, a mutant insulin promoter that lacked the PDX-1 binding site was not stimulated by TGF-beta. In summary, the results of these studies show that TGF-beta stimulates the transcription of insulin gene and this action is mediated by the transcription factor, PDX-1.
Sayo
Y
Y
First Department of Internal Medicine, Kagawa Medical University, Kagawa, Japan. sayo@kms.ac.jp
Hosokawa
H
H
Imachi
H
H
Murao
K
K
Sato
M
M
Wong
N C
NC
Ishida
T
T
Takahara
J
J
D000818:Animals; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism*; D020104:Immunophilins / Q000235:genetics; D007328:Insulin / Q000235:genetics*; D007340:Insulinoma; D007515:Islets of Langerhans / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D016559:Tacrolimus / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018398:Homeodomain Proteins; D007328:Insulin; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C084010:pancreatic and duodenal homeobox 1 protein; D004247:DNA; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D005947:Glucose; D016559:Tacrolimus