INSERTIONAL ACTIVATION OF MEVALONATE KINASE BY HEPATITIS-B VIRUS-DNA IN A HUMAN HEPATOMA-CELL LINE

Insertional mutagenesis of growth related genes by hepatitis B virus ( HBV) DNA is presumed to play a role in hepatocarcinogenesis. Here, we report on insertional activation of the mevalonate kinase (MK) gene in the human hepatoma cell line PLC/PRF/5, Integration of HBV DNA dissoc iated the promoter and upstream regulatory elements of the gene from i ts coding sequences. This led to the over-expression of hybrid transcr ipts arising from an HBV promoter and the consequent over-production o f functionally active mevalonate kinase. MK phosphorylates mevalonate, a major intermediate in the branched cholesterol/isoprenoid biosynthe tic pathway. Isoprenylation is crucial to the functions of cellular pr oteins related to growth control, including the proto-oncogene ras. As the enzymes of these biosynthetic pathways are regulated at multiple points by negative feedback, both transcriptionally and at the protein level, the results discussed here support the idea that aberrant grow th could result from deregulated overexpression of MK and, perhaps, ot her enzymes in the cholesterol pathway. These results invoke novel mec hanisms by which cell transformation might occur.