The role of calcium/calmodulin-dependent protein kinase cascade in glucose upregulation of insulin gene expression

Xiao Yu, Koji Murao, Yoshitaka Sayo, Hitomi Imachi, Wen M. Cao, Shouji Ohtsuka, Michio Niimi, Hiroshi Tokumitsu, Hiroyuki Inuzuka, Norman C.W. Wong, Ryoji Kobayashi, Toshihiko Ishida

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26 Citations (Scopus)

Abstract

A number of factors have been reported to affect insulin synthesis in β-cells. Although glucose is the most important regulator of insulin gene expression in pancreatic β-cells, the mechanisms whereby glucose stimulates insulin gene transcription in response to changes in glucose concentration have not been clarified yet. In this study, we examined the role of the Ca2+/calmodulin (CaM)-dependent protein kinase (CaM-K) cascade in transcriptional activation of insulin. RT-PCR, Western blotting, and immunohistochemical staining analysis revealed that CaM-K kinase-α (CaM-KKα) and CaM-KIV were localized in rat pancreatic β-cells and their cell line, INS-1. Exposure of INS-1 cells to 11.2 mmol/l glucose elicited an increase of insulin promoter activity as well as upregulation of CaM-KIV activity within 2 min after stimulation. We investigated the influence on insulin promoter activity of the constitutively active form (CaM-KIVc) or dominant-negative mutant (CaM-KIVdn) of CaM-KIV in transfected INS-1 cells. CaM-KIVc alone was sufficient, and the upstream kinase, CaM-KK, was enhanced to upregulate the insulin promoter activity in INS-1 cells. Furthermore, cotransfection of CaM-KIVdn suppressed to a significant degree the glucose-upregulated activity of the insulin promoter. Taken together, these results indicated that the CaM-KK/CaM-KIV cascade might play an important role in glucose-upregulated transcriptional activation of the insulin gene.

Original languageEnglish
Pages (from-to)1475-1481
Number of pages7
JournalDiabetes
Volume53
Issue number6
DOIs
Publication statusPublished - Jun 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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  • Cite this

    Yu, X., Murao, K., Sayo, Y., Imachi, H., Cao, W. M., Ohtsuka, S., Niimi, M., Tokumitsu, H., Inuzuka, H., Wong, N. C. W., Kobayashi, R., & Ishida, T. (2004). The role of calcium/calmodulin-dependent protein kinase cascade in glucose upregulation of insulin gene expression. Diabetes, 53(6), 1475-1481. https://doi.org/10.2337/diabetes.53.6.1475