Mechanisms controlling the KEAP1-NRF2 signaling pathway in lung cancer Public Deposited

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  • March 22, 2019
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  • Hast, Bridgid Elizabeth
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • An ability to effectively regulate intracellular reactive oxygen species is imperative to prevent conditions of oxidative stress, and ultimately aberrant cell death. The primary means by which cells control reactive species is through the KEAP1-NRF2 signaling pathway. NRF2 is a transcription factor that is constitutively degraded by the E3 ubiquitin ligase adaptor KEAP1 under homeostatic conditions. When intracellular levels of reactive oxygen species rise, these reactive molecules inactivate KEAP1, thus inhibiting degradation of NRF2. NRF2 then translocates to the nucleus where it drives transcription of several genes including reactive oxygen species-scavenging genes, drug efflux genes, and cell survival genes. NRF2 interacts with KEAP1 via two amino acid motifs, the ETGE and DLG, which position NRF2 in a sterically favorable position for ubiquitination. An emerging alternative mechanism for activation of NRF2, referred to as the Competitive Binding Mechanism, has been proposed. This mode of NRF2 activation relies on KEAP1 interacting proteins that contain a motif similar to the ETGE motif of NRF2, which compete with NRF2 for binding to KEAP1. We have identified several KEAP1 interacting proteins that bind to KEAP1 in an ETGE-dependent manner, including the dipeptidase DPP3. Identification of these interacting proteins not only validate the Competitive Binding Model, but also introduce DPP3 as a protein relevant in NRF2 activation in cancer. In addition to competitive binding, somatic mutations in KEAP1 have also been shown to activate NRF2. Unlike activating mutations in NRF2, which cluster to the ETGE and DLG motifs, mutations in KEAP1 are present throughout the entirety of the protein. How these somatic mutations affect KEAP1 function is currently not known. We have characterized 18 mutations in KEAP1 derived from The Cancer Genome Atlas lung squamous cell carcinoma cohort. In addition to determining that the majority of KEAP1 mutations are hypomorphic, we also identify a novel class of KEAP1 mutations that bind NRF2 and facilitate its ubiquitination, but cannot degrade NRF2.
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  • In Copyright
Advisor
  • Major, Michael
Degree
  • Doctor of Philosophy
Graduation year
  • 2013
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