NFAT Regulates Insulin Gene Promoter Activity in Response to Synergistic Pathways Induced by Glucose and Glucagon-Like Peptide-1
-
- Michael C. Lawrence
- From the Department of Molecular Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Texas
-
- Harshika S. Bhatt
- From the Department of Molecular Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Texas
-
- Richard A. Easom
- From the Department of Molecular Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Texas
抄録
<jats:p>Currently there is intense interest to define the mechanism of action of glucagon-like peptide-1 (GLP-1) in regulating β-cell function, including insulin gene transcription. In this study, GLP-1 (100 nmol/l), in the presence of glucose (11 mmol/l), induced a ∼71-fold increase in insulin gene promoter activity in INS-1 pancreatic β-cells, an effect that was an order of magnitude larger than with either stimulant alone. The response to GLP-1 was mimicked by forskolin and largely inhibited by the protein kinase A (PKA) inhibitors, H89 and myristoylated PKI(14–22) amide, indicating partial mediation via a cAMP/PKA pathway. Significantly, the actions of both GLP-1 and forskolin were abolished by the selective Ca2+/calmodulin-dependent phosphatase 2B (calcineurin) inhibitor, FK506, as well as by the chelation of intracellular Ca2+ by BAPTA (bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetate). Glucose and GLP-1 also synergistically activated NFAT (nuclear factor of activated T-cells)-mediated transcription from a minimal promoter construct containing tandem NFAT consensus sequences. Furthermore, two-point base pair mutations in any of the three identified NFAT sites within the rat insulin I promoter resulted in a significant reduction in the combined effect of glucose and GLP-1. These data suggest that the synergistic action of glucose and GLP-1 to promote insulin gene transcription is mediated through NFAT via PKA- and calcineurin-dependent pathways in pancreatic β-cells.</jats:p>
収録刊行物
-
- Diabetes
-
Diabetes 51 (3), 691-698, 2002-03-01
American Diabetes Association
- Tweet
詳細情報 詳細情報について
-
- CRID
- 1360292621336293760
-
- NII論文ID
- 30026273415
-
- ISSN
- 1939327X
- 00121797
- http://id.crossref.org/issn/00121797
-
- データソース種別
-
- Crossref
- CiNii Articles