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The GI-GPx gene is a target for Nrf2
Antje Banning1, Stefanie Deubel, Dirk Kluth
1German Institute of Human Nutrition, Potsdam-Rehbruecke, Dept. of Biochemistry and Micronutrients, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
Molecular and Cellular Biology
|June 1, 2005
Summary
Gastrointestinal glutathione peroxidase (GI-GPx, GPx2) is upregulated by antioxidants like sulforaphane, potentially mediating their anti-inflammatory and anti-cancer effects. This occurs via the Nrf2 pathway, highlighting GI-GPx
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Gastrointestinal glutathione peroxidase (GI-GPx, GPx2) is a selenoprotein involved in cellular protection.
- GI-GPx has been linked to controlling inflammation and malignant growth.
- Its induction by antioxidants suggests a role in the Nrf2/Keap1 pathway.
Purpose of the Study:
- To investigate the regulation of GI-GPx by the antioxidant response element (ARE) and the Nrf2/Keap1 system.
- To validate the functional significance of the ARE in the GI-GPx promoter.
- To explore the role of GI-GPx in mediating the effects of natural antioxidants.
Main Methods:
- Reporter gene assays in CaCo-2 cells to assess transcriptional activation.
- Mutation of the ARE in the GI-GPx promoter to determine its necessity.
- Chromatin immunoprecipitation to confirm Nrf2 binding to the gpx2 gene.
- Treatment with electrophiles (tBHQ, SFN, curcumin) and manipulation of Nrf2/Keap1 levels.
Main Results:
- GI-GPx expression was induced by electrophilic compounds (tBHQ, SFN) and Nrf2 overexpression.
- A functional ARE in the GI-GPx promoter was confirmed through reporter gene assays.
- Nrf2 binding to the ARE in the gpx2 gene was validated by chromatin immunoprecipitation.
- Effects were reversed by mutating the ARE or overexpressing Keap1.
Conclusions:
- The Nrf2/Keap1 pathway, via the ARE, significantly regulates GI-GPx expression.
- Natural antioxidants like sulforaphane and curcumin up-regulate GI-GPx.
- GI-GPx induction may contribute to the anti-inflammatory and anticarcinogenic properties of these antioxidants.
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