Doria, M., Klein, N., Lucito, R., Schneider, R. J. (October 1995) The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors. Embo J, 14 (19). pp. 4747-57.
Abstract
The HBx protein of hepatitis B virus (HBV) is a transcriptional activator that is required for infection and may play an important role in HBV-associated hepatocarcinogenesis. Recently, we and others have shown that HBx stimulates the Ras-Raf-MAP kinase cascade, which leads to enhanced cell proliferation and the activation of transcription factors AP-1 and NF-kappa B. Other studies have shown that HBx can activate transcription by interacting directly with nuclear components of the transcription machinery. Therefore we examined the basis for the different reported activities of HBx. Here, we show that HBx is a complex protein, displaying independent activities in different intracellular locations. The intracellular distribution of HBx protein was first investigated using scanning confocal laser immunomicroscopy and by genetic studies. Our work has established that HBx expressed in cultured cells is found authentically in both the cytoplasm and the nucleus. HBx is not strongly associated with any intracellular structures, but some preferential accumulation was observed near the cell surface. Next, HBx variants were constructed containing a functional or mutant nuclear localization sequence. We show that when HBx is engineered to relocate exclusively to the nucleus, it no longer activates the Ras-Raf-MAP kinase cascade, nor does it activate transcription factors AP-1 and NF-kappa B. Surprisingly, nuclear HBx fully retains the ability to stimulate HBV enhancer I, which is activated independently of the Ras and protein kinase C pathways. Therefore HBx protein stimulates signal transduction pathways in the cytoplasm and transactivates transcription elements in the nucleus. Furthermore, SV40 T antigen is shown to induce the nuclear sequestration of HBx protein and to block its activation of NF-kappa B, demonstrating that HBx is regulated by proteins that alter its intracellular distribution. The conflicting functions of HBx protein in viral infection and possibly carcinoma may involve the regulation of its differential distribution in the cell.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Amino Acid Sequence Antigens Polyomavirus Transforming physiology Base Sequence Ca(2+) Calmodulin Dependent Protein Kinase physiology Cell Nucleus chemistry Cytoplasm chemistry Enhancer Elements Genetics Hepatitis B virus Humans Molecular Sequence Data NF-kappa B Protein Serine Threonine Kinases physiology Proto Oncogene Proteins physiology Proto Oncogene Proteins c-raf Proto-Oncogene Proteins p21(ras) Recombinant Fusion Proteins biosynthesis Signal Transduction physiology Simian virus 40 immunology Trans-Activation (Genetics) physiology genetics Trans-Activators analysis genetics physiology Transcription Factor AP-1 |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor organism description > virus |
| CSHL Authors: | |
| Communities: | CSHL labs > Lucito lab |
| Depositing User: | Brian Soldo |
| Date: | 2 October 1995 |
| Date Deposited: | 29 Mar 2012 15:06 |
| Last Modified: | 04 Apr 2012 20:34 |
| URI: | https://repository.cshl.edu/id/eprint/25557 |
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