NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer

John D. Hayes, Michael McMahon

    Research output: Contribution to journalReview article

    584 Citations (Scopus)

    Abstract

    Transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2) controls cellular adaptation to oxidants and electrophiles by inducing antioxidant and detoxification genes in response to redox stress. NRF2 is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1). Tumours from similar to 15% of patients with lung cancer harbour somatic mutations in KEAP1 that prevent effective NRF2 repression. Recently, two NRF2 mutation 'hot-spots' were identified in similar to 10% of patients with lung cancer, enabling the transcription factor to evade KEAP1-mediated repression. Somatic mutations in KEAP1 and NRF2 provide an insight into the molecular mechanisms by which NRF2 is regulated. Moreover, constitutive NRF2 activation might cause drug resistance in tumours, and an understanding of how the transcription factor is regulated indicates ways in which this could be overcome.

    Original languageEnglish
    Pages (from-to)176-188
    Number of pages13
    JournalTrends in Biochemical Sciences
    Volume34
    Issue number4
    DOIs
    Publication statusPublished - Apr 2009

    Keywords

    • TRANSCRIPTION FACTOR NRF2
    • GLUTATHIONE S-TRANSFERASES
    • CHEMOPREVENTIVE AGENT SULFORAPHANE
    • DRUG-METABOLIZING-ENZYMES
    • UBIQUITIN LIGASE COMPLEX
    • CUL3-BASED E3 LIGASE
    • ANTIOXIDANT RESPONSE
    • OXIDATIVE STRESS
    • GENE-EXPRESSION
    • LUNG-CANCER

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