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10:36
Measurements of Physiological Stress Responses in C. Elegans
Published on: May 21, 2020
A small-molecule inducer of the antioxidant response element
Wooyoung Hur1, Zheng Sun, Tao Jiang
1Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Chemistry & Biology
|June 11, 2010
Summary
Researchers discovered AI-1, a novel compound that activates the Nrf2 pathway by modifying Keap1. This activation enhances cellular antioxidant responses and holds therapeutic potential for various diseases.
Area of Science:
- Molecular Biology
- Cellular Stress Response
Background:
- Eukaryotic cells utilize the Nrf2-ARE pathway to combat oxidative stress.
- Nrf2 controls protective enzyme expression by binding to the antioxidant response element (ARE).
- Electrophilic molecules activating Nrf2 show therapeutic promise in tumor models.
Purpose of the Study:
- To identify novel activators of the Nrf2 pathway.
- To investigate the mechanism of action of a newly discovered class of ARE activators, termed AI-1.
Main Methods:
- High-throughput cellular screening to identify ARE activators.
- Biochemical assays to elucidate the molecular mechanism of AI-1 action.
- Investigation of Keap1 modification and its effect on Nrf2 stabilization.
Main Results:
- A new class of ARE activators, AI-1, was discovered.
- AI-1 activates Nrf2 by covalently modifying Keap1 at Cys151.
- Modification of Keap1 by AI-1 disrupts its function as a Cul3-Keap1 ubiquitin ligase adaptor.
- This disruption leads to Nrf2 stabilization and transcriptional activation.
Conclusions:
- AI-1 represents a novel mechanism for Nrf2 activation.
- AI-1's ability to modify Keap1 offers a new strategy for modulating cellular antioxidant responses.
- AI-1 and its derivatives serve as valuable tools for studying the Nrf2 pathway.
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