Peroxisome proliferators are a class of hepatic carcinogens in rodents and have been proposed to act in part by increasing oxidative stress. Fatty acyl CoA oxidase (FAO), which is highly induced by peroxisome proliferators, is the hydrogen peroxide-generating enzyme of the peroxisomal beta-oxidation pathway. We previously showed that the treatment of rats and mice with the peroxisome proliferator ciprofibrate resulted in increased hepatic NF-kappaB activity and suggested that this effect may be secondary to the action of H2O-generating enzymes. To test this possibility directly, we have determined whether transient overexpression of FAO, in the absence of peroxisome proliferators, leads to NF-kappaB activation. Here, we show that FAO overexpression in Cos-1 cells, in the presence of an H2O-generating substrate, can activate a NF-kappaB regulated reporter gene. Electrophoretic mobility shift assays further demonstrated that FAO expression increases nuclear NF-kappaB DNA binding activity in a dose-dependent manner. The antioxidants vitamin E and catalase can inhibit this activation. These results indicate that FAO mediates, at least in part, peroxisome proliferator-induced NF-kappaB activation.

Integration of mouse endogenous retroviral (MERV) elements is responsible for an estimated 10% of spontaneous mutations that have been characterized in the laboratory mouse. We recently identified a MERV integration in the first intron of the Zinc fingers and homeoboxes 2 (Zhx2) gene in BALB/cJ mice, resulting in reduced Zhx2 expression. This integration is found in BALB/cJ but not in other BALB/c substrains, indicating that it occurred after these substrains separated in the late 1930s. We have characterized this MERV element and show here that it belongs to the ETnII-alpha class of elements. Our analysis reveals that the Zhx2 ETn element lacks a 69-bp sequence compared to most other ETn elements which may be due to recombination between two identical 13-bp elements. Three mature Zhx2 transcripts are found in the liver of BALB/cJ mice. The major transcript is spliced from Zhx2 exon 1 to the 5' ETn LTR and is polyadenylated at the 3' LTR. Of the two less abundant transcripts, one is identical to the wild-type transcript, whereas the second contains 183 bp of ETn sequence spliced between Zhx2 exons 1 and 2. We have also sequenced and analyzed products from the fas ( lpr ) ETn found in MRL/lpr mice and show that it belongs to the ETnII-beta class of elements.

No abstract