Antitumor promotion by phenolic antioxidants: inhibition of AP-1 activity through induction of Fra expression.

Abstract

Induction of phase 2 detoxification enzymes by phenolic antioxidants can account for prevention of tumor initiation but cannot explain why these compounds inhibit tumor promotion. Phase 2 genes are induced through an antioxidant response element (ARE). Although the ARE resembles an AP-1 binding site, we show that the major ARE binding and activating protein is not AP-1. Interestingly, AP-1 DNA binding activity was induced by the phenolic antioxidant tert-butylhydroquinone (BHQ), but the induction of AP-1 transcriptional activity by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) was inhibited by this compound. BHQ induced expression of c-jun, junB, fra-1, and fra-2, which encode AP-1 components, but was a poor inducer of c-fos and had no effect on fosB. Like c-Fos and FosB, the Fra proteins heterodimerize with Jun proteins to form stable AP-1 complexes. However, Fra-containing AP-1 complexes have low transactivation potential. Furthermore, Fra-1 repressed AP-1 activity induced by either TPA or expression of c-Jun and c-Fos. We therefore conclude that inhibitory AP-1 complexes composed of Jun-Fra heterodimers, induced by BHQ, antagonize the transcriptional effects of the tumor promoter TPA, which are mediated by Jun-Fos heterodimers. Since AP-1 is an important mediator of tumor promoter action, these findings may explain the anti-tumor-promoting activity of phenolic antioxidants.

• Authors: K Yoshioka, T Deng, M Cavigelli, M Karin
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 92 Issue 11 Pg. 4972-6 (May 23 1995) ISSN: 0027-8424 [Print] United States
• PMID: 7761434 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anticarcinogenic Agents
• Antioxidants
• DNA-Binding Proteins
• FOSL2 protein, human
• Fos-Related Antigen-2
• Fosl2 protein, mouse
• Hydroquinones
• Oligonucleotide Probes
• Proto-Oncogene Proteins c-fos
• Transcription Factor AP-1
• Transcription Factors
• fos-related antigen 1
• 2-tert-butylhydroquinone
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Anticarcinogenic Agents (pharmacology)
• Antioxidants (pharmacology)
• Base Sequence
• DNA-Binding Proteins (biosynthesis)
• Fos-Related Antigen-2
• Gene Expression (drug effects)
• Genes, fos (drug effects)
• Genes, jun (drug effects)
• HeLa Cells
• Humans
• Hydroquinones (pharmacology)
• Mice
• Molecular Sequence Data
• Oligonucleotide Probes
• Oxidation-Reduction
• Proto-Oncogene Proteins c-fos (biosynthesis)
• Proto-Oncogenes (drug effects)
• Tetradecanoylphorbol Acetate (pharmacology)
• Transcription Factor AP-1 (antagonists & inhibitors)
• Transcription Factors (biosynthesis)
• Transcription, Genetic
• Tumor Cells, Cultured