title: MicroRNA-7 activates Nrf2 pathway by targeting Keap1 expression.
abstract: Nuclear factor E2-related factor 2 (Nrf2) is a key transcription factor that regulates the expression of a number of antioxidant and detoxifying genes that provide cellular protection against various stressors including reactive oxygen species (ROS). Nrf2 activity is tightly regulated by a cytoplasmic inhibitory protein called Kelch-like ECH-associated protein 1 (Keap1). The mechanism that controls Keap1 expression, however, remains poorly understood. In the present study, we demonstrate that microRNA-7 (miR-7), which is highly expressed in the brain, represses Keap1 expression by targeting the 3'-untranslated region (UTR) of its mRNA in human neuroblastoma cells, SH-SY5Y. Subsequently, this event results in an increased Nrf2 activity, as evidenced by an increase in the expression of its transcriptional targets, heme oxygenase 1 (HO-1) and glutamate-cysteine ligase modifier subunit (GCLM), and an enhanced nuclear localization of Nrf2. In addition, miR-7 decreases the intracellular hydroperoxides level and increases the level of reduced form of glutathione, indicative of oxidative stress relief. We also demonstrate that targeted repression of Keap1 and activation of Nrf2 pathway, in part, underlies the protective effects of miR-7 against 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity in SH-SY5Y and differentiated human neural progenitor cells, ReNcell VM. These findings point to a new mechanism by which miR-7 exerts cytoprotective effects by regulating the Nrf2 pathway.
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ., 08854, USA.
authors.forename: Savan
authors.initials: S
authors.lastname: Kabaria
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ., 08854, USA.
authors.forename: Doo Chul
authors.initials: DC
authors.lastname: Choi
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ., 08854, USA.
authors.forename: Amrita Datta
authors.initials: AD
authors.lastname: Chaudhuri
authors.affiliation: Center for Advanced Proteomics Research, Rutgers-New Jersey Medical School, Newark, NJ., 07103, USA.
authors.forename: Mohit Raja
authors.initials: MR
authors.lastname: Jain
authors.affiliation: Center for Advanced Proteomics Research, Rutgers-New Jersey Medical School, Newark, NJ., 07103, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ., 08854, USA. Electronic address: junneu@rwjms.rutgers.edu.
authors.forename: Eunsung
authors.initials: E
authors.lastname: Junn
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D002853:Chromatography, Liquid; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D000072019:Kelch-Like ECH-Associated Protein 1; D035683:MicroRNAs / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D053719:Tandem Mass Spectrometry; D014162:Transfection
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; C431364:KEAP1 protein, human; C549242:MIRN7-1 microRNA, human; C495635:NFE2L2 protein, human
keywords: Keap1; MPP+; MicroRNA-7; Nrf2; Oxidative stress; Parkinson's disease