title: Competition of nuclear factor-erythroid 2 factors related transcription factor isoforms, Nrf1 and Nrf2, in antioxidant enzyme induction.
abstract: Although the Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) regulated expression of multiple antioxidant and cytoprotective genes through the electrophile responsive element (EpRE) is well established, interaction of Nrf2/EpRE with Nrf1, a closely-related transcription factor, is less well understood. Due to either proteolysis or alternative translation, Nrf1 has been found as proteins of varying size, p120, p95, and p65, which have been described as either activators of EpRE or competitive inhibitors of Nrf2. We investigated the effect of Nrf1 on EpRE-regulated gene expression using the catalytic and modifier subunits of glutamate cysteine ligase (GCLC and GCLM) as models and explored the potential role of Nrf1 in altering their expression in aging and upon chronic exposure to airborne nano-sized particulate matter (nPM). Nrf1 knockout resulted in the increased expression of GCLC and GCLM in human bronchial epithelial (HBE1) cells. Overexpression Nrf2 in combination with either p120 or p65 diminished or failed to further increase the GCLC- and GLCM-EpRE luciferase activity. All known forms of Nrf1 protein, remained unchanged in the lungs of mice with age or in response to nPM. Our study shows that Nrf1 could inhibit EpRE activity in vitro, whereas the precise role of Nrf1 in vivo requires further investigations. We conclude that Nrf1 may not be directly responsible for the loss of Nrf2-dependent inducibility of antioxidant and cytoprotective genes observed in aged animals.
authors.affiliation: Institute of Biochemistry and Department of Biology, Carleton University, Ottawa, ON, Canada, K1S 5B6.
authors.forename: Nikolai L
authors.initials: NL
authors.lastname: Chepelev
authors.forename: Hongqiao
authors.initials: H
authors.lastname: Zhang
authors.forename: Honglei
authors.initials: H
authors.lastname: Liu
authors.forename: Skye
authors.initials: S
authors.lastname: McBride
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Seal
authors.forename: Todd E
authors.initials: TE
authors.lastname: Morgan
authors.forename: Caleb E
authors.initials: CE
authors.lastname: Finch
authors.forename: William G
authors.initials: WG
authors.lastname: Willmore
authors.forename: Kelvin J A
authors.initials: KJ
authors.lastname: Davies
authors.forename: Henry Jay
authors.initials: HJ
authors.lastname: Forman
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D005721:Glutamate-Cysteine Ligase / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000235:genetics* / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics* / Q000378:metabolism*; D052638:Particulate Matter / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020218:Response Elements
chemical_list: D000975:Antioxidants; D050984:NF-E2 Transcription Factor, p45 Subunit; D051266:Nuclear Respiratory Factor 1; D052638:Particulate Matter; D020033:Protein Isoforms; D005721:Glutamate-Cysteine Ligase
keywords: Air pollution; ER, endoplasmic reticulum; Electrophile response element; EpRE, electrophile response element; GCL, glutamate cysteine ligase; GCLC, catalytic subunit of GCL; GCLM, modifier subunit of GCL; Glutamate cysteine ligase; HBE1, human bronchial epithelial cells; HO-1, heme oxygenase; Nrf1; Nrf1, nuclear factor-erythroid 2 p45 subunit-related factor 1; Nrf2; Nrf2, nuclear factor-erythroid 2 p45 subunit-related factor 2; Phase II genes; nPM, nanoparticulate air pollution
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