1. Intracellular Accumulation of Middle Hepatitis B Surface Protein Activates Gene Transcription
- Author
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Volker Schlüter, Rajen Koshy, Markus Meyer, Christian Rabe, and Wolfgang H. Caselmann
- Subjects
Transcriptional Activation ,Carcinoma, Hepatocellular ,KDEL ,Enzyme-Linked Immunosorbent Assay ,Biology ,Endoplasmic Reticulum ,Transactivation ,Genes, Reporter ,Transcription (biology) ,Tumor Cells, Cultured ,Humans ,Secretion ,Transcription factor ,Secretory pathway ,DNA Primers ,Hepatitis B Surface Antigens ,Endoplasmic reticulum ,Liver Neoplasms ,Gastroenterology ,DNA, Neoplasm ,General Medicine ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Oxidative Stress ,Cell Transformation, Neoplastic ,Intracellular ,Plasmids ,Transcription Factors - Abstract
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, MHBst167, is not secreted but retained within the secretory pathway. Here, we provide evidence that when full-length MHBs is coexpressed with the truncated MHBst167 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 MHBst167 in enhancing the nuclear-binding activity of transcription factors NFĸB and AP-1, and activation of NFĸB- and AP-1-dependent transcription of reporter genes. As is the case for MHBst167, MHBsKDEL-dependent activation of NFĸB 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.
- Published
- 2001
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