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

Abstract

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 GSTP1 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 GSTP1 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.

• Authors: Annelyse Duvoix, Michaël Schnekenburger, Sylvie Delhalle, Romain Blasius, Patricia Borde-Chiché, Franck Morceau, Mario Dicato, Marc Diederich
• Journal: Cancer letters (Cancer Lett) Vol. 216 Issue 2 Pg. 207-19 (Dec 28 2004) ISSN: 0304-3835 [Print] Ireland
• PMID: 15533597 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hydroquinones
• Isoenzymes
• Transcription Factor AP-1
• Doxorubicin
• Hydrogen Peroxide
• 2-tert-butylhydroquinone
• GSTP1 protein, human
• Glutathione S-Transferase pi
• Glutathione Transferase
• Tetradecanoylphorbol Acetate

Topics

• Binding Sites
• Doxorubicin (pharmacology)
• Electrophoretic Mobility Shift Assay
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glutathione S-Transferase pi
• Glutathione Transferase (biosynthesis, genetics)
• Humans
• Hydrogen Peroxide (pharmacology)
• Hydroquinones (pharmacology)
• Isoenzymes (biosynthesis, genetics)
• Jurkat Cells
• K562 Cells
• Leukemia
• Mutagenesis, Site-Directed
• Promoter Regions, Genetic
• Tetradecanoylphorbol Acetate (pharmacology)
• Transcription Factor AP-1 (biosynthesis, genetics, metabolism)
• Transcription, Genetic
• Transfection
• U937 Cells