THE HEPATITIS-B VIRUS TRANSACTIVATOR HBX CAUSES ELEVATION OF DIACYLGLYCEROL AND ACTIVATION OF PROTEIN-KINASE-C

Chronic infection with hepatitis B virus (HBV) is accompanied by an in creasing risk of developing hepatocellular carcinoma. There are indica tions that the HBx protein of HBV is involved in the process of tumour formation. HBx also transactivates several transcription factor bindi ng sites. Recently, we reported that HBx can use a tumour promotor pat hway for transactivation. In particular, we found that transactivation of the binding motif for transcription factor AP-1 (JUN/FOS) by HBx i s dependent on functional protein kinase C (PKC), as indicated by abol ition of the transcriptional stimulation following downregulation or i nhibition of the enzyme. Moreover, HBx activates PKC, probably via inc reasing the endogenous PKC activator sn-1,2-diacylglycerol (DAG). Here we extend these data and report on the time course of PKC activation. We found that activation of PKC by HBx is transient and differs from activation of PKC by the ras oncogene product or phorbol ester in that it does not lead to rapid downregulation of the enzyme subsequent to the activation. Moreover, we provide evidence that an increase in cell ular DAG is observable not only as an early event in response to HBx b ut also in cell lines transformed after transfection with HBV DNA and stably expressing HBx. Besides its important role in the regulation of cellular genes, PKC is also the intracellular receptor for tumour-pro moting agents and an activator of proto-oncogenes, suggesting that our observations might provide an explanation for the oncogenic propertie s of HBx.