THE HNF1 HNF4-DEPENDENT WE2 ELEMENT OF WOODCHUCK HEPATITIS-VIRUS CONTROLS VIRAL REPLICATION AND CAN ACTIVATE THE N-MYC2 PROMOTER/

Transcriptional activation of myc family proto-oncogenes through the i nsertion of viral sequences is the predominant mechanism by which wood chuck hepatitis virus (WHV) induces liver tumors in chronically infect ed animals. The main target is N-myc2, a functional retroposon of the N-myc gene, but c-myc and N-myc are also marginally involved. Here we identify a major, liver-specific regulatory element in the WHV genome (We2) which efficiently activates the N-myc2 promoter in cultured hepa toma cells. In the context of the episomal viral genome, We2 governs t he production of pregenomic RNA and thus plays a central role in the c ontrol of viral replication, We2 activity is primarily controlled by t he liver-enriched HNF1 and HNF4 transcription factors, although NF1 an d Oct proteins were also shown to bind in a central region. The expres sion of HNF1 and HNF4 appears to be maintained in woodchuck tumors. Th us, We2 is a prime candidate for controlling myc gene cis activation d uring WHV-induced hepatocarcinogenesis.