Tumor promoter arsenite stimulates histone H3 phosphoacetylation of proto-oncogenes c-fos and c-jun chromatin in human diploid fibroblasts.

Abstract

Although epidemiological studies have long established that inorganic arsenic is a potent human carcinogen, the underlying mechanisms are still poorly understood. Recent studies suggest that inorganic arsenic may act as a tumor promoter by perturbing key signaling transduction pathways. We have shown previously that arsenite can potently activate the mitogen-activated protein kinase cascades and induce the expression of proliferation-associated genes, including proto-oncogenes c-jun and c-fos. In order to elucidate further the molecular mechanisms underlying its tumor-promoting properties, we investigated the signaling events involved in arsenite-mediated induction of c-fos and c-jun. We found that induction of both c-fos and c-jun by arsenite can be substantially inhibited by the MEK- selective inhibitor U0126, suggesting that the ERK pathway is critically involved in their up-regulation. Interestingly, arsenite dramatically induced the phosphorylation and acetylation of histone H3 preceding the induction of mRNAs encoding c-fos and c-jun. Finally, chromatin immunoprecipitation assays revealed that arsenite treatment markedly induced the phosphorylation/acetylation of histone H3 associated with the c-fos and c-jun genes through an ERK-dependent pathway. Our results strongly suggest that arsenic-triggered alterations in chromatin structure perturb specific gene transcription, including that of proto-oncogenes c-jun and c-fos, and may thereby contribute to the carcinogenic process.

• Authors: Ji Li, Myriam Gorospe, Janice Barnes, Yusen Liu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 15 Pg. 13183-91 (Apr 11 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12547826 (Publication Type: Journal Article)

Chemical References

• Arsenites
• Butadienes
• Carcinogens
• Chromatin
• DNA Primers
• Enzyme Inhibitors
• Histones
• Nitriles
• RNA, Messenger
• U 0126
• Phosphoserine
• Ribosomal Protein S6 Kinases, 90-kDa
• mitogen and stress-activated protein kinase 1
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• arsenite

Topics

• Acetylation
• Arsenites (pharmacology)
• Base Sequence
• Butadienes (pharmacology)
• Carcinogens (pharmacology)
• Cell Cycle (drug effects)
• Chromatin (drug effects, metabolism)
• DNA Primers
• Diploidy
• Enzyme Inhibitors (pharmacology)
• Fibroblasts (drug effects, metabolism)
• Genes, fos
• Genes, jun
• Histones (metabolism)
• Humans
• Kinetics
• Mitogen-Activated Protein Kinases (antagonists & inhibitors)
• Nitriles (pharmacology)
• Phosphorylation
• Phosphoserine (metabolism)
• Polymerase Chain Reaction
• RNA, Messenger (genetics)
• Ribosomal Protein S6 Kinases, 90-kDa (antagonists & inhibitors, metabolism)
• Transcription, Genetic
• p38 Mitogen-Activated Protein Kinases