期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 12, 页码 10449-10456出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.209510
关键词
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资金
- MEXT, Japan
- Mitsubishi Foundation
- Takeda Science Foundation
- Japan Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [11J40085, 22590982] Funding Source: KAKEN
Pancreatic beta-cell-restricted expression of insulin is established through several critical cis-regulatory elements located in the insulin gene promoter region. The principal cis elements are A-boxes, E1, and C1/RIPE3b. The beta-cell-enriched transcription factors Pdx1 and Beta2 bind to the A-boxes and E1 element, respectively. A beta-cell-specific trans-acting factor binding to C1/RIPE3b (termed RIPE3b1 activator) was detected by electrophoretic mobility shift assay and has been identified as MafA, a member of the Maf family of basic leucine zipper (bZip) proteins. Here, ATF2, a member of the ATF/CREB family of basic leucine zipper proteins, was identified as a component of the RIPE3b1 activator. ATF2 alone was unable to bind to the C1/RIPE3b element but acquired binding capacity upon complex formation with MafA. ATF2 also interacted with Pdx1 and Beta2, and co-expression of ATF2, MafA, Pdx1, and Beta2 resulted in a synergistic activation of the insulin promoter. Immunohistochemical analysis of mouse pancreas tissue sections showed that ATF2 is enriched in islet endocrine cells, including beta-cells. RNAi-mediated knockdown of MafA or ATF2 in the MIN6 beta-cell line resulted in a significant decrease in endogenous levels of insulin mRNA. These data indicate that ATF2 is an essential component of the positive regulators of the insulin gene expression.
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