Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2147155 | Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis | 2008 | 6 Pages |
Abstract
Exposure to benzene, a ubiquitous environmental pollutant, has been linked to leukemia, although the mechanism of benzene-initiated leukemogenesis remains unclear. Benzene can be bioactivated to toxic metabolites such as 1,4 benzoquinone (BQ), which can alter signaling pathways and affect chromosomal integrity. BQ has been shown to increase the activity of c-Myb, which is an important transcription factor involved in hematopoiesis, cell proliferation, and cell differentiation. The c-Myb protein has also been shown to increase topoisomerase IIα (Topo IIα) promoter activity specifically in cell lines with hematopoietic origin. Topo IIα is a critical nuclear enzyme that removes torsional strain by cleaving, untangling and religating double-stranded DNA. Since Topo IIα mediates DNA strand breaks, aberrant Topo IIα activity or increased protein levels may increase the formation of DNA strand breaks, leaving the cell susceptible to mutational events. We hypothesized that BQ can increase c-Myb activity, which in turn increases Topo IIα promoter activity resulting in increased DNA strand breaks. Using luciferase reporter assays in K-562 cells we demonstrated that BQ (25 and 37 μM) exposure caused an increase in c-Myb activity after 24 h. Contradictory to previous findings, overexpression of exogenous c-Myb or a polypeptide consisting of c-Myb's DNA binding domain (DBD), which competitively inhibits the binding of endogenous c-Myb to DNA, did not affect Topo IIα promoter activity. However, BQ (37 μM for 24 h) exposure caused a significant increase in Topo IIα promoter activity, which could be blocked by the overexpression of the DBD polypeptide, suggesting that BQ exposure increases Topo IIα promoter activity through the c-Myb signaling pathway.
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Authors
Roopam Singh, Louise M. Winn,