MafK overexpression in pancreatic beta-cells caused impairment of glucose-stimulated insulin secretion.
MafA is a member of large Maf transcription factors and activates the insulin gene in pancreatic beta-cells. Other large Maf transcription factors, MafB and c-Maf, also express and activate insulin transcription in beta-cells. However, the functional relationship between MafA and other Maf proteins in beta-cells has not been established. In order to suppress the function of large Maf proteins, we generated transgenic mice overexpressing MafK, which act as dominant negative protein in pancreatic beta-cells. These mice showed hyperglycemia at a young age due to impairment of glucose-stimulated insulin secretion. Although the transgenic mice showed an abnormal response in the glucose tolerance test, hyperglycemia was restored in adulthood. Histological analysis revealed islet hypertrophy in adult transgenic mice. Finally, an electrophoretic gel mobility shift assay showed that the DNA-binding activity of endogenous MafA was significantly increased in the MafK transgenic mice. These results indicated that MafA may have relevance to compensatory response.
Shimohata
Homare
H
Department of Anatomy and Embryology, Biomolecular and Integrated Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
Yoh
Keigyou
K
Morito
Naoki
N
Shimano
Hitoshi
H
Kudo
Takashi
T
Takahashi
Satoru
S
D000375:Aging / Q000502:physiology; D000818:Animals; D001835:Body Weight; D048430:Cell Shape; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology*; D006943:Hyperglycemia / Q000097:blood / Q000473:pathology; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000494:pharmacology; D050985:MafK Transcription Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020218:Response Elements / Q000235:genetics
D007328:Insulin; D051473:Maf Transcription Factors, Large; D050985:MafK Transcription Factor; C485160:Mafa protein, mouse; D005947:Glucose