Nrf2b: novel zebrafish paralog of the oxidant-responsive transcription factor NF-E2-related factor 2 (NRF2)

Timme-Laragy, A.R., Karchner, S.I., Franks, D.G., Jenny, M.J., Harbeitner, R.C., Goldstone, J.V., McArthur, A.G., and Hahn, M.E.
The Journal of biological chemistry   287(7): 4609-4627 (Journal)
Registered Authors
Franks, Diana, Goldstone, Jed, Hahn, Mark E., Karchner, Sibel
aryl hydrocarbon receptor, gene expression, Nrf2, oxidative stress, zebrafish, antioxidant response element
MeSH Terms
  • Animals
  • Antioxidants/pharmacology
  • Embryo, Nonmammalian/metabolism*
  • Gene Duplication
  • Gene Expression Regulation, Enzymologic/drug effects
  • Gene Expression Regulation, Enzymologic/physiology
  • Gene Knockdown Techniques
  • Humans
  • Hydroquinones/pharmacology
  • Morpholinos/pharmacology
  • NF-E2-Related Factor 2/genetics*
  • NF-E2-Related Factor 2/metabolism*
  • Oxidation-Reduction/drug effects
  • Oxidative Stress/drug effects
  • Oxidative Stress/physiology
  • Protein Structure, Tertiary
  • Zebrafish/embryology*
  • Zebrafish/genetics*
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism*
  • tert-Butylhydroperoxide/pharmacology
22174413 Full text @ J. Biol. Chem.

NF-E2-related factor 2 (NRF2, also called NFE2L2) and related NRF family members regulate antioxidant defenses by activating gene expression via antioxidant response elements (AREs), but their roles in embryonic development are not well understood. We report here that zebrafish (Danio rerio), an important developmental model species, possesses six nrf genes, including duplicated nrf1 and nrf2 genes. We cloned a novel zebrafish nrf2 paralog, nrf2b. The predicted Nrf2b protein sequence shares several domains with the original Nrf2 (now Nrf2a), but lacks the Neh4 transactivation domain. Zebrafish-human comparisons demonstrate conserved synteny involving nrf2 and hox genes, indicating that nrf2a and nrf2b are co-orthologs of human NRF2. nrf2a and nrf2b displayed distinct patterns of expression during embryonic development; nrf2b was more highly expressed at all stages. Embryos in which Nrf2a expression had been knocked down with morpholino oligonucleotides were more sensitive to tert-butylhydroperoxide (tBOOH) but not tert-butyl hydroquinone (tBHQ), whereas knockdown of Nrf2b did not affect sensitivity of embryos to either chemical. Gene expression profiling by microarray identified a specific role for Nrf2b as a negative regulator of several genes including p53, cyclin g1, and heme oxygenase 1 in embryos. Nrf2a and Nrf2b exhibited different mechanisms of crosstalk with the Ahr2 signaling pathway. Together, these results demonstrate distinct roles for nrf2a and nrf2b, consistent with subfunction partitioning, and identify a novel negative regulatory role for Nrf2b during development. The identification of zebrafish nrf2 co-orthologs will facilitate new understanding of the multiple roles of NRF2 in protecting vertebrate embryos from oxidative damage.

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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes