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Final Published Version
Author
Shakya, A.Liu, P.
Godek, J.
McKee, N.W.
Dodson, M.
Anandhan, A.
Ooi, A.
Garcia, J.G.N.
Costa, M.
Chapman, E.
Zhang, D.D.
Affiliation
Department of Pharmacology and Toxicology, College of Pharmacy, University of ArizonaIssue Date
2023-09
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Elsevier B.V.Citation
Shakya, Aryatara, et al. "The NRF2-p97-NRF2 negative feedback loop." Redox Biology 65 (2023): 102839.Journal
Redox BiologyRights
© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
p97 is a ubiquitin-targeted ATP-dependent segregase that regulates proteostasis, in addition to a variety of other cellular functions. Previously, we demonstrated that p97 negatively regulates NRF2 by extracting ubiquitylated NRF2 from the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, facilitating proteasomal destruction. In the current study, we identified p97 as an NRF2-target gene that contains a functional ARE, indicating the presence of an NRF2-p97-NRF2 negative feedback loop that maintains redox homeostasis. Using CRISPR/Cas9 genome editing, we generated endogenous p97 ARE-mutated BEAS-2B cell lines. These p97 ARE-mutated cell lines exhibit altered expression of p97 and NRF2, as well as a compromised response to NRF2 inducers. Importantly, we also found a positive correlation between NRF2 activation and p97 expression in human cancer patients. Finally, using chronic arsenic-transformed cell lines, we demonstrated a synergistic effect of NRF2 and p97 inhibition in killing cancer cells with high NRF2 and p97 expression. Our study suggests dual upregulation of NRF2 and p97 occurs in certain types of cancers, suggesting that inhibition of both NRF2 and p97 could be a promising treatment strategy for stratified cancer patients. © 2023Note
Open access journalISSN
2213-2317PubMed ID
37573837Version
Final Published Versionae974a485f413a2113503eed53cd6c53
10.1016/j.redox.2023.102839
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Except where otherwise noted, this item's license is described as © 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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