Gene regulatory effects of disease-associated variation in the NRF2 network

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14 Scopus citations

Abstract

Reactive oxygen species (ROS), which are both a natural byproduct of oxidative metabolism and an undesirable byproduct of many environmental stressors, can damage all classes of cellular macromolecules and promote diseases from cancer to neurodegeneration. The actions of ROS are mitigated by the transcription factor NRF2, which regulates expression of antioxidant genes via its interaction with cis-regulatory antioxidant response elements (AREs). However, despite the seemingly straightforward relationship between the opposing forces of ROS and NRF2, regulatory precision in the NRF2 network is essential. Genetic variants that alter NRF2 stability or alter ARE sequences have been linked to a range of diseases. NRF2 hyperactivating mutations are associated with tumorigenesis. On the subtler end of the spectrum, single nucleotide variants (SNVs) that alter individual ARE sequences have been linked to neurodegenerative disorders including progressive supranuclear palsy and Parkinson's disease, as well as other diseases. Although the human health implications of NRF2 dysregulation have been recognized for some time, a systems level view of this regulatory network is beginning to highlight key NRF2-targeted AREs consistently associated with disease.

Original languageEnglish (US)
Pages (from-to)71-79
Number of pages9
JournalCurrent Opinion in Toxicology
Volume1
DOIs
StatePublished - 2016

Bibliographical note

Funding Information:
We apologize to our colleagues whose work is not cited herein due to space limitations. This work was supported by funding from the National Institutes of Health (R35GM119553 to MS), the Whiteside Institute for Clinical Research (MS), and the University of Minnesota Foundation (MS).

Publisher Copyright:
© 2016 The Authors

Keywords

  • ARE
  • Cancer
  • GWAS
  • MAPT
  • Mutation
  • NFE2L2
  • NRF2
  • Oxidative stress
  • Parkinson disease
  • Polymporphism

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