The role of c-MYB in benzene-initiated toxicity.
Chronic exposure to benzene has been correlated with increased oxidative stress and leukemia. Oncogene activation, including c-Myb activation, is one of the earliest steps leading to the formation of leukemic cells, however the molecular mechanisms involved in these events are poorly understood. Given that oxidative stress can alter the activity and fate of cell signaling pathways we hypothesize that the bioactivation of benzene leads to the formation of reactive oxygen species (ROS), which if not detoxified can alter the c-Myb signaling pathway. Using chicken erythroblast HD3 cells we have shown that exposure to the benzene metabolites catechol, benzoquinone, and hydroquinone leads to increased c-Myb activity, increased phosphorylation of c-Myb and increased production of ROS supporting our hypothesis. Activation of the aryl hydrocarbon receptor (AhR) by environmental contaminants has also been associated with carcinogenesis and mice lacking this receptor are resistant to benzene-initiated hematotoxicity. Using wild type and AhR deficient cells we are investigating the role of this receptor in benzene-initiated alterations in the c-Myb signaling pathway. We have found that both wild type and AhR deficient cells are sensitive to catechol and hydroquinone-initiated increases in c-Myb activity while both cell types are resistant to benzene-initiated alterations leaving the role of the AhR still undetermined. Interestingly, protein expression of c-Myb is increased after catechol exposure in AhR deficient cells while decreased in wild-type cells. Further studies on the role of the AhR in benzene-initiated alterations on the c-Myb signaling pathway are on going.
Wan
Joanne
J
Department of Pharmacology and Toxicology and School of Environmental Studies, Queen's University, Botterell Hall Room 557, Kingston, Ont., Canada K7L 3N6.
Badham
Helen J
HJ
Winn
Louise
L
D000818:Animals; D001554:Benzene / Q000378:metabolism / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects*; D020598:Proto-Oncogene Proteins c-myb / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D020598:Proto-Oncogene Proteins c-myb; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D001554:Benzene