Intracellular accumulation of middle hepatitis B surface protein activates gene transcription.
While the natural intact protein does not possess any transactivator function, C-terminal truncation of the middle hepatitis B surface (MHBs) protein yields a novel transactivator function. We have previously found that the truncated transactivator protein, MHBs(t167), is not secreted but retained within the secretory pathway. Here, we provide evidence that when full-length MHBs is coexpressed with the truncated MHBs(t167) protein, the secretion of the full-length protein is inhibited and both proteins accumulate within the cell. We further show that MHBs, forcibly retained in the cell by C-terminal fusion to the endoplasmic reticulum retention signal KDEL (MHBsKDEL), mimics the effects of MHBs(t167) in enhancing the nuclear-binding activity of transcription factors NFkappaB and AP-1, and activation of NFkappaB- and AP-1-dependent transcription of reporter genes. As is the case for MHBs(t167), MHBsKDEL-dependent activation of NFkappaB is inhibited by the antioxidant N-acetyl-L-cysteine indicating the involvement of reactive oxygen intermediates and suggesting a similar mechanism of activation. This study suggests that the intracellular retention and accumulation of the normally secreted MHBs leads to oxidative stress and activation of transcription. This may be an important but not exclusive mechanism in hepatocarcinogenesis.
Schlüter
V
V
Department of Virus Research, Max Planck Institute of Biochemistry, Martinsried, Germany.
Rabe
C
C
Meyer
M
M
Koshy
R
R
Caselmann
W H
WH
D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000821:virology*; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006514:Hepatitis B Surface Antigens / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology*; D018384:Oxidative Stress; D010957:Plasmids; D014157:Transcription Factors / Q000494:pharmacology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D004273:DNA, Neoplasm; D006514:Hepatitis B Surface Antigens; D014157:Transcription Factors