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Marked increase of insulin gene transcription by suppression of the Rho/Rho-kinase pathway.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2006 Nov 10; Vol. 350 (1), pp. 68-73. Date of Electronic Publication: 2006 Sep 12. - Publication Year :
- 2006
-
Abstract
- The hallmarks of type 2 diabetes are pancreatic beta-cell dysfunction and insulin resistance. It has been suggested that Rho/Rho-kinase is a mediator of insulin signaling, and thereby involved in the development of insulin resistance, regulation of insulin action, and glucose homeostasis, but the role of Rho/Rho-kinase in beta-cells remained unknown. The aim of this study was to examine the possible role of Rho/Rho-kinase in beta-cell function. Immunostaining showed that RhoA was expressed in mature beta-cells, with higher expression observed in beta-cells of diabetic C57BL/KsJ-db/db mice compared to non-diabetic mice. In addition, to examine the functional role of Rho/Rho-kinase in beta-cells, we evaluated the effect of Rho-kinase inhibitors on insulin biosynthesis. Northern blot analysis showed that insulin mRNA levels were markedly increased by Rho-kinase inhibitors, Y-27632 and fasudil, in beta-cell-derived HIT-T15 cells. Furthermore, using the luciferase reporter gene assay, insulin promoter activity was also dramatically increased by Y-27632, which was associated with an increase in the insulin mRNA level. These results suggest that suppression of Rho/Rho-kinase increases insulin promoter activity, which leads to an increase in insulin mRNA level. Taken together, Rho/Rho-kinase is activated in beta-cells under diabetic conditions and suppression of the Rho/Rho-kinase pathway increases insulin gene transcription. These results imply that Rho/Rho-kinase activation is involved in the suppression of insulin expression found in diabetes and that suppression of the Rho/Rho-kinase pathway could be a useful tool to augment insulin gene transcription.
- Subjects :
- Animals
Cell Line
DNA metabolism
Diabetes Mellitus metabolism
Homeodomain Proteins metabolism
Humans
Intracellular Signaling Peptides and Proteins metabolism
Maf Transcription Factors, Large metabolism
Mice
Pancreas metabolism
Promoter Regions, Genetic genetics
Protein Kinase Inhibitors pharmacology
Protein Serine-Threonine Kinases metabolism
RNA, Messenger genetics
RNA, Messenger metabolism
Trans-Activators metabolism
rho GTP-Binding Proteins metabolism
rho-Associated Kinases
Insulin genetics
Intracellular Signaling Peptides and Proteins antagonists & inhibitors
Protein Serine-Threonine Kinases antagonists & inhibitors
Signal Transduction
Transcription, Genetic genetics
rho GTP-Binding Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0006-291X
- Volume :
- 350
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 16996478
- Full Text :
- https://doi.org/10.1016/j.bbrc.2006.08.192