THE BPV-4 COCARCINOGEN QUERCETIN INDUCES CELL-CYCLE ARREST AND UP-REGULATES TRANSCRIPTION FROM THE LCR OF BPV-4

Bracken fern is the environmental co-carcinogen of BPV-4 in the induct ion of neoplasias of the upper alimentary canal of cattle. The flavono id quercetin is one of the most potent and best characterised mutagens present in the fern. We have shown that transfection with BPV-4 DNA a nd exposure to a single dose of quercetin leads to tumorigenic transfo rmation of primary bovine cells. We now show that quercetin induces ce ll cycle arrest and up-regulates transcription from the BPV-4 long con trol region (LCR). This up-regulation is mediated by a 21 nucleotide-l ong cis-element in the LCR, designated QRE-1, which is located immedia tely downstream of the TATA box. Cellular proteins bind to QRE-1 and r emoval or substitution of QRE-1 lead to the abrogation of the response to quercetin. As expression of the viral oncogenes is controlled by t he LCR, perturbation in this control and increased oncoprotein express ion are likely to contribute to fully malignant cell transformation by overcoming the cell cycle arrest induced by quercetin, thus forcing d amaged cells to proliferate.