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Polymorphic electrophile response elements in the mouse glutathione S-transferase GSTa1 gene that confer increased
M Zhu1, W G Chapman, M J Oberley
1McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706, USA.
Cancer Letters
|February 17, 2001
Summary
Naturally occurring genetic variations in the electrophile responsive element (EpRE) can alter the expression of protective genes. This polymorphism in EpRE may influence cancer risk by affecting drug-metabolizing enzyme induction.
Area of Science:
- Genetics
- Molecular Biology
- Pharmacology
Background:
- The electrophile responsive element (EpRE) regulates stress response genes, including drug-metabolizing enzymes.
- Previous studies showed that mutations in EpRE affect gene expression.
Purpose of the Study:
- To investigate naturally occurring EpRE sequence variations.
- To determine if EpRE polymorphisms influence the expression of glutathione S-transferases (GSTs) and impact cancer risk.
Main Methods:
- Screened 32 mouse strains and species for EpRE sequence variations in the mGSTa1 promoter.
- Utilized reporter gene assays in HepG2 cells to assess variant EpRE inducibility.
- Compared mGSTa1 mRNA levels in mouse livers.
Main Results:
- Identified TGAC to TGGC mutations in the EpRE of Mus caroli and Mus spretus.
- The variant Mus spretus EpRE showed significantly increased inducibility (15-fold) compared to wild-type (8-fold).
- Mus spretus and Mus caroli mice exhibited higher mGSTa1 mRNA levels in their livers.
Conclusions:
- Naturally occurring EpRE polymorphism was identified.
- This polymorphism is associated with altered gene inducibility and higher mGSTa1 expression.
- This finding represents the first reported mutation in a promoter regulatory element of a drug-metabolizing gene with an associated phenotype.
