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Related Experiment Video

Updated: Jul 19, 2025

Monitoring Protein-RNA Interaction Dynamics In Vivo at High Temporal Resolution Using χCRAC

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Published on: May 9, 2020

The NRF2-p97-NRF2 negative feedback loop.

Aryatara Shakya¹, Pengfei Liu², Jack Godek¹

¹Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA.

|August 13, 2023

Summary

This summary is machine-generated.

The protein p97 negatively regulates NRF2, but NRF2 also targets p97, creating a feedback loop. This dual upregulation in cancer suggests inhibiting both NRF2 and p97 may be a treatment strategy.

Keywords:

Arsenic Cancer Nrf2 Oxidative stress Proteostasis p97

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Published on: November 15, 2013

Area of Science:

Cellular biology
Molecular mechanisms of proteostasis
Redox homeostasis

Background:

p97 (VCP) is an ATP-dependent segregase involved in proteostasis.
p97 negatively regulates NRF2 by promoting its proteasomal degradation.
NRF2 is a key transcription factor in cellular defense against oxidative stress.

Purpose of the Study:

To investigate the regulatory relationship between p97 and NRF2.
To elucidate the role of the NRF2-p97-NRF2 feedback loop in redox homeostasis.
To explore the therapeutic potential of targeting NRF2 and p97 in cancer.

Main Methods:

CRISPR/Cas9 genome editing to mutate the ARE in the p97 gene.
Analysis of p97 and NRF2 expression in engineered cell lines and human cancer patient data.
Assessment of synergistic effects of NRF2 and p97 inhibition in cancer cells.

Main Results:

p97 was identified as an NRF2 target gene, establishing a negative feedback loop.
p97 ARE-mutated cells showed altered p97/NRF2 expression and impaired NRF2 response.
A positive correlation between NRF2 activation and p97 expression was observed in human cancers.
Combined inhibition of NRF2 and p97 synergistically killed cancer cells with high expression of both.

Conclusions:

A novel NRF2-p97-NRF2 negative feedback loop maintains redox homeostasis.
Dual upregulation of NRF2 and p97 is implicated in certain cancers.
Simultaneous inhibition of NRF2 and p97 presents a potential therapeutic strategy for specific cancer patient populations.