Analysis of the Upstream Elements of the Xenobiotic Compound-Inducible and Positionally Regulated Glutathione S-Transferase Ya Gene

Abstract

In situ hybridization and other data showed that all hepatocytes express glutathione-S-transferase (GST) Ya mRNA but that specifically pericentral cells can be induced 15- to 20-fold with 3-methylcholanthrene (3-MC). In order to identify DNA sequences involved in inducible expression (pericentral hepatocytes) and constitutive expression (all hepatocytes), the upstream regions of the GST Ya gene were further analyzed by transient transfection and DNA-binding studies to identify the nature of proteins involved in regulating this gene. The sequences from −980 to −650 were necessary and sufficient for cell-specific and inducible expression. Within this enhancer region, four nuclear protein-binding sites were identified. One site required for inducible expression was bound by a protein(s) induced by 3-MC. Two other sites were bound by proteins similar or identical to the constitutive hepatocyte nuclear factors HNF1 and HNF4. The fourth site was shown to be bound by a non-liver-specific nuclear protein that is also important in the function of the albumin gene enhancer.