Abstract:
AIMS/HYPOTHESIS:Mutations in the islet amyloid polypeptide ( IAPP) gene may play a potential role in the abnormal regulation or expression of the peptide. The aim of this study was to determine the functional role of the -132 G/A mutation reported in the promoter region of the IAPP gene in a population of Spanish Type 2 diabetic patients. METHODS:We investigated the transcriptional activity using MIN6 cells and luciferase reporter plasmids in several culture conditions. Key regulatory elements of the IAPP promoter region were also analysed by electrophoretic mobility shift assays (EMSA). RESULTS:The mutant construct doubled IAPP transcriptional activity ( p<0.001). Both constructs showed severely reduced promoter activity (four-fold decrease) in the presence of verapamil and diazoxide. In contrast, IAPP promoter activity was doubled after incubation with forskolin or dexamethasone, regardless of the glucose concentrations in the culture media. EMSA revealed that the -132 G/A mutation increased the binding affinity through two DNA-protein complexes. In addition, a cAMP-responsive element binding protein (CREB) was identified by super-shift EMSA. CONCLUSIONS/INTERPRETATION:Our studies show that the wild-type and the mutant constructs are regulated in a similar pattern under all conditions, strongly indicating that the -132 G/A mutation increases basal but not inducible transcription. These results may be explained by new binding to the mutant region through CREB and other transcription factors not yet identified.
journal_name
Diabetologiajournal_title
Diabetologiaauthors
Novials A,Mato E,Lucas M,Franco C,Rivas M,Santisteban P,Gomis Rdoi
10.1007/s00125-004-1439-ysubject
Has Abstractpub_date
2004-07-01 00:00:00pages
1167-1174issue
7eissn
0012-186Xissn
1432-0428pii
10.1007/s00125-004-1439-yjournal_volume
47pub_type
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