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Blood, 1 July 2005, Vol. 106, No. 1, pp. 304-310. Prepublished online as a Blood First Edition Paper on March 10, 2005; DOI 10.1182/blood-2005-01-0241.
NEOPLASIA Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidationFrom the Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei; Graduate Institute of Epidemiology, National Taiwan University, Taipei; and the Department of Medicine, Program of Human Genetics and Molecular Biology, Institute for Cell Engineering, and the Kimmel Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD.
The mechanism by which arsenic dramatically affects gene expression remains poorly understood. Here we report that prolonged exposure of acute promyelocytic leukemia NB4 cells to low levels of arsenic trioxide increased the expression of a set of genes responsible for reactive oxygen species (ROS) production. We hypothesize that arsenic-induced ROS in turn contribute partially to altered gene expression. To identify genes responsive to arsenic-induced ROS, we used microarray gene expression analysis and identified genes that responded to arsenic and hydrogen peroxide but whose response to arsenic was reversed by an ROS scavenger, N-acetyl-L-cysteine. We found that 26% of the genes significantly responsive to arsenic might have been directly altered by ROS. We further explored the mechanisms by which ROS affects gene regulation and found that the Sp1 transcription factor was oxidized by arsenic treatment, with a corresponding decrease in its in situ binding on the promoters of 3 genes, hTERT, C17, and c-Myc, whose expressions were significantly suppressed. We conclude that ROS contributed partly to arsenic-mediated gene regulation and that Sp1 oxidation contributed to gene suppression by arsenic-induced ROS.
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