Repression of insulin gene transcription by indirect genomic signaling via the estrogen receptor in pancreatic beta cells View Full Text


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Article Info

DATE

2019-04

AUTHORS

Takashi Sekido, Shin-ichi Nishio, Yohsuke Ohkubo, Keiko Sekido, Junichiro Kitahara, Takahide Miyamoto, Mitsuhisa Komatsu

ABSTRACT

The mechanism whereby 17β-estradiol (E2) mediates insulin gene transcription has not been fully elucidated. In this study, exposure of hamster insulinoma (HIT-T15) cells to 5 × 10-9 to 1 × 10-7 M E2 led to a concentration-dependent decrease of insulin mRNA levels. Transient expression of the estrogen receptor (ER) in HIT-T15 cells revealed that estrogen receptor α (ERα) repressed transcription of the rat insulin II promoter in both ligand-dependent and ligand-independent manners. The N-terminal A/B domain of ERα was not required for either activity. However, the repression was absent with mutated ER lacking the DNA-binding domain. Moreover, introducing mutations in the D-box and P-box of the zinc finger of ER (C227S, C202L) also abolished the repression. Deletion of the insulin promoter region revealed that nucleotide positions - 238 to - 144 (relative to the transcriptional start site) were needed for ER repression of the rat insulin II gene. PDX1- and BETA2-binding sites were required for the repression, but an estrogen response element-like sequence or an AP1 site in the promoter was not involved. In conclusion, we found that estrogen repressed insulin mRNA expression in a beta cell line. In addition, the ER suppressed insulin gene transcription in a ligand-independent matter. These observations suggest ER may regulate insulin transcription by indirect genomic signaling. More... »

PAGES

226-236

Journal

Author Affiliations

From Grant

  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s11626-019-00328-5

    DOI

    http://dx.doi.org/10.1007/s11626-019-00328-5

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1112283319

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30790128


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