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.

Extreme clonal uniformity of Phoxinus eos/neogaeus gynogens (pisces: Cyprinidae) among variable habitats in northern Minnesota beaver ponds.

Genetic surveys of parthenogenetic vertebrate populations have demonstrated a common pattern of relatively high degrees of clonal variation and the coexistence of numerous clones. In striking contrast, the Phoxinus eos/Phoxinus neogaeus/hybrid gynogen complex of cyprinid fishes exhibits no clonal variation within a northern Minnesota drainage characterized by successional beaver ponds. Gynogens were sampled from three habitats in each of four different pond types in a single drainage in Voyageurs National Park, Minnesota. The abundance of gynogens relative to sexual dace varied with pond type, being least common in deep upland ponds and most common in shallow, collapsed, lowland ponds (13.4% and 48.6%, respectively). Simple-sequence multilocus DNA fingerprinting of 464 individual gynogens detected one, and only one, clone. DNA fingerprints, generated sequentially by using three oligonucleotide probes, (CAC)5, (GACA)4, and the Jeffreys' 33.15 probe, all revealed the same unprecedented lack of variation. The extreme lack of clonal diversity in these gynogens across a range of habitat types does not fit the general pattern of high clonal diversity found within populations of other vertebrate parthenogens.