Antitumor promotion by phenolic antioxidants: inhibition of AP-1 activity through induction of Fra expression.
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.
Yoshioka
K
K
Department of Pharmacology, University of California, San Diego, La Jolla 92093-0636, USA.
Deng
T
T
Cavigelli
M
M
Karin
M
M
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D051921:Fos-Related Antigen-2; D015870:Gene Expression / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D010084:Oxidation-Reduction; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D011519:Proto-Oncogenes / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000099169:Fos-Related Antigen 1
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D004268:DNA-Binding Proteins; D051921:Fos-Related Antigen-2; D006873:Hydroquinones; D015345:Oligonucleotide Probes; D016760:Proto-Oncogene Proteins c-fos; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000099169:Fos-Related Antigen 1; C497872:FOSL2 protein, human; C497873:Fosl2 protein, mouse; C018855:2-tert-butylhydroquinone