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The PreS2 activator MHBs t of hepatitis B virus activates c‐raf‐1/Erk2 signaling in transgenic mice
Author(s) -
Hildt Eberhard,
Munz Barbara,
Saher Gesine,
Reifenberg Kurt,
Hofschneider Peter Hans
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/21.4.525
Subject(s) - biology , virology , transgene , activator (genetics) , genetically modified mouse , microbiology and biotechnology , virus , gene , genetics
The large hepatitis B virus (HBV) surface protein (LHBs) and C‐terminally truncated middle size surface proteins (MHBs t ) form the family of the PreS2 activator proteins of HBV. Their transcriptional activator function is based on the cytoplasmic orientation of the PreS2 domain. MHBs t activators are paradigmatic for this class of activators. Here we report that MHBs t is protein kinase C (PKC)‐dependently phosphorylated at Ser28. The integrity of the phosphorylation site is essential for the activator function. MHBs t triggers PKC‐dependent activation of c‐Raf‐1/Erk2 signaling that is a prerequisite for MHBs t ‐dependent activation of AP‐1 and NF‐κB. To analyze the pathophysiological relevance of these data in vivo , transgenic mice were established that produce the PreS2 activator MHBs t specifically in the liver. In these mice, a permanent PreS2‐dependent specific activation of c‐Raf‐1/Erk2 signaling was observed, resulting in an increased hepatocyte proliferation rate. In transgenics older than 15 months, an increased incidence of liver tumors occurs. These data suggest that PreS2 activators LHBs and MHBs t exert a tumor promoter‐like function by activation of key enzymes of proliferation control.