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Increased gene expression in human promyeloid leukemia cells exposed to trans,trans-muconaldehyde, a hematotoxic benzene metabolite.

Abstract
The hematotoxicity of benzene, a human leukemogen, has been postulated to be mediated by reactive metabolites and involve cell damage caused by reactive oxygen species. Because expression of the transcription factors AP-1 and NF-kappaB is sensitive to the redox state in eukaryotic cells, the DNA binding activity of AP-1 and NF-kappaB was examined in HL-60 promyeloid leukemia cells exposed to trans,trans-muconaldehyde, a microsomal hematotoxic metabolite of benzene. There was little AP-1 binding activity in nuclear extracts from control HL-60 cells based on electrophoretic mobility shift assays. Exposure to 0.1 microM MUC for 4 h resulted in significantly increased levels of nuclear protein with high sequence specificity for the consensus AP-1 sequence. In addition, electrophoretic mobility shift assays showed a strong increase in the binding of a factor to the NF-kappaB site. The latter was highest in nuclear extracts from HL-60 cells treated with 1.0 microM muconaldehyde and cultured for 4 h. Exposure of HL-60 cells to muconaldehyde resulted in an increase in c-fos and c-jun mRNA levels. Western blot analysis showed that the protein levels of c-jun increased in HL-60 cells treated with 1 microM muconaldehyde and cultured for 4-6 h and subsequently decreased gradually. Increased AP-1 binding was observed in bone marrow cells from B6C3F1 mice 2 h after administration of 440 mg/kg benzene. We suggest that increased gene expression of NF-kappaB and AP-1 binding activity and up-regulation of c-fos and c-jun may play a role in the mechanism of benzene leukemogenesis.
AuthorsT Y Ho, G Witz
JournalCarcinogenesis (Carcinogenesis) Vol. 18 Issue 4 Pg. 739-44 (Apr 1997) ISSN: 0143-3334 [Print] England
PMID9111208 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Aldehydes
  • NF-kappa B
  • RNA, Messenger
  • Transcription Factor AP-1
  • muconaldehyde
  • DNA
  • Benzene
Topics
  • Aldehydes (toxicity)
  • Animals
  • Benzene (toxicity)
  • Bone Marrow (drug effects, metabolism)
  • DNA (metabolism)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Genes, fos
  • Genes, jun
  • HL-60 Cells
  • Humans
  • Mice
  • NF-kappa B (metabolism)
  • Protein Binding
  • RNA, Messenger (genetics, metabolism)
  • Transcription Factor AP-1 (metabolism)
  • Up-Regulation

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