Expression of glutathione S-transferase P1-1 in leukemic cells is regulated by inducible AP-1 binding

Glutathione S-transferases (GST) are involved in cellular protection against xenobiotics, oxidative stress as well as in resistance against chemotherapeutic compounds such as doxorubicin. Levels of human placental type GSTP1-1 are known to be increased in many tumors and hematopoietic diseases. In this work, we compare transcriptional mechanisms in cells that express or not GSTP1-1. Transient transfection assays are used to show that different GST-promoter reporter constructs generate cell-type specific levels of luciferase activity. In expressing cells, transcriptional activity is strongly dependent on AP-1 binding elements within the -65 to -75 bp region of the GSTPI gene as shown by site-directed mutagenesis. Electrophoretic mobility shift assays show that DNA binding activity is exclusively observed in GSTP1-1-expressing cells and is increased after stimulation with hydrogen peroxide, TPA, tert-butylhydroquinone and doxorubicin. Non-expressing cells present neither constitutive nor inducible AP-1 binding. Taken together, our results provide evidence for the induction of the GSTPI gene via AP-1 binding activity in leukemia cells and contribute to a better understanding of the molecular events regulating genes involved in drug resistance mechanisms. (C) 2004 Elsevier Ireland Ltd. All rights reserved.