Regulation of Insulin Gene Transcription by a Ca2+-Responsive Pathway Involving Calcineurin and Nuclear Factor of Activated T Cells
- 1 October 2001
- journal article
- Published by The Endocrine Society in Molecular Endocrinology
- Vol. 15 (10) , 1758-1767
- https://doi.org/10.1210/me.15.10.1758
Abstract
Immunosuppressants such as FK506 (tacrolimus), the primary cellular target of which is calcineurin, decrease -cell insulin content and preproinsulin mRNA expression. This study offers an explanation for this effect by establishing that calcineurin is an important regulator of insulin gene expression through the activation of a transcription factor, nu- clear factor of activated T cells. Three putative nuclear factor of activated T cells binding sites were located within the proximal region of the rat insulin I gene promoter (410 to 1 bp). Expres- sion of nuclear factor of activated T cells in both clonal (INS-1) and primary (islet) -cells was con- firmed by immunoblot and immunocytochemical analyses. Moreover, nuclear factor of activated T cells DNA-binding activity was detected in INS-1 and islet nuclear extracts by EMSAs. Activation of the insulin gene promoter by glucose or elevated extracellular K (to depolarize the -cell) was to- tally prevented by FK506 (5-10 M). K-induced promoter activation was suppressed (>65%) by a 2-bp mutation of a single nuclear factor of acti- vated T cells binding site in 410 rInsI. Both stim- ulants also activated a minimal promoter-reporter construct containing tandem nuclear factor of ac- tivated T cells consensus sequences. The effects of FK506 on K-induced nuclear factor of activated T cells reporter or insulin gene promoter activity were not mimicked by rapamycin, indicating spec- ificity toward calcineurin. These findings suggest that the activation of calcineurin by -cell secreta- gogues that elevate cytosolic Ca2 plays a funda- mental role in maintenance of insulin gene expres- sion via the activation of nuclear factor of activated T cells. (Molecular Endocrinology 15: 1758-1767, 2001)Keywords
This publication has 0 references indexed in Scilit: