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 increasing risk of developing hepatocellular carcinoma. There are indications that the HBx protein of HBV is involved in the process of tumour formation. HBx also transactivates several transcription factor binding sites. Recently, we reported that HBx can use a tumour promotor pathway for transactivation. In particular, we found that transactivation of the binding motif for transcription factor AP-1 (JUN/FOS) by HBx is dependent on functional protein kinase C (PKC), as indicated by abolition of the transcriptional stimulation following downregulation or inhibition of the enzyme. Moreover, HBx activates PKC, probably via increasing 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 cellular DAG is observable not only as an early event in response to HBx but 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-promoting agents and an activator of proto-oncogenes, suggesting that our observations might provide an explanation for the oncogenic properties of HBx.
Luber
B
B
Max-Planck-Institut für Biochemie, Martinsried, Germany.
Lauer
U
U
Weiss
L
L
Höhne
M
M
Hofschneider
P H
PH
Kekulé
A S
AS
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase; D004075:Diglycerides / Q000378:metabolism*; D004789:Enzyme Activation; D017930:Genes, Reporter; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000166:cytology; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D011493:Protein Kinase C / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D051381:Rats; D015534:Trans-Activators / Q000235:genetics*; D015533:Transcriptional Activation; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins
D004075:Diglycerides; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D015500:Chloramphenicol O-Acetyltransferase; D011493:Protein Kinase C