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miR‐125b transcriptionally induced by Nrf2 inhibits AhR repressor for AhR activation (663.12)
Author(s) -
Joo Min Sung,
Lee Chan Gyu,
Koo Ja Hyun,
Kim Sang Geon
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.663.12
Subject(s) - microrna , chemistry , toxicant , transfection , repressor , downregulation and upregulation , microbiology and biotechnology , luciferase , cancer research , biology , gene , toxicity , gene expression , biochemistry , organic chemistry
MicroRNAs (miRNAs) play a role in the cellular defense mechanism. Nrf2 may control cell survival against toxicant challenge. miRNA transcriptionally controlled by Nrf2 had not been characterized. In this study, we explored the miRNAs regulated by Nrf2 and the responsible biological function. Bioinformatic approaches enabled us to extract 6 candidate miRNAs. Of them, only miR‐125b was increased in the kidney of mice treated with oltipraz. Nrf2 overexpression enhanced primary, precursor and mature miR‐125b levels. Functional assays revealed MIR125B1 is a bona fide target gene of Nrf2. Oltipraz treatment protected the kidney from cisplatin toxicity with increase of miR‐125b. Consistently, Nrf2 knockout abrogated an adaptive increase of miR‐125b by cisplatin, augmenting kidney injury. An integrative network of miRNA and mRNA changes enabled us to predict miR‐125b as an inhibitor of AhRR and cell survival. In the experiments using 3′‐UTR reporter, miR‐125b mimic and its inhibitor, miR‐125b inhibited AhRR, activating AhR, which caused the induction of mdm2. Consequently, p53 activation by cisplatin was diminished by either miR‐125b transfection or oltipraz treatment. In summary, miR‐125b is transcriptionally activated by Nrf2 and serves as an inhibitor of AhRR, which contributes to the protection of cell from injury.