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Integrity of c-Raf-1/MEK signal transduction cascade is essential for hepatitis B virus gene expression

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Abstract

The genome of hepatitis B virus (HBV) encodes two transcriptional activators: the HBx protein and the PreS2-activator large surface protein (LHBs). Both proteins trigger activation of c-Raf-1/MEK kinase cascade. In case of HBx this can be mediated by a PKC-independent and Ras-dependent mechanism, in case of LHBs activation is PKC-dependent and does not require Ras. Selective destruction of either LHBs- or of HBx-specific activation does not result in significant decrease of viral production from transfected HepG2 cells. Simultaneous inhibition of LHBs- and HBx-dependent activation by blocking signaling steps common to both activators, using trans dominant negative c-Raf-1- or MEK-specific inhibitors, abolished HBV gene expression. In accordance with this no HBV propagation was observed after transfection of a mutated HBV genome defective for HBx- and PreS2-activator function. A detailed analysis revealed that the observed inhibition of HBV- propagation is because of a significant reduction of HBV-specific RNA resulting in an inhibition of the de novo synthesis of viral compounds (viral proteins and nucleic acid) and not by blocking secretion or assembly of the virus. Based on these results we conclude that transcriptional-activator function, mediated by the c-Raf-1/MEK signaling cascade, is essential for HBV gene expression.

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References

  • Andrisani OM and Barnabas S . (1999). Int. J. Oncol., 15, 373–379.

  • Benn J and Schneider RJ . (1994). Proc. Natl. Acad. Sci. USA, 91, 10350–10354.

  • Bouchard M, Wang EH and Schneider RJ . (2001). Science, 294, 2376–2378.

  • Bruder JT, Heidecker G and Rapp UR . (1992). Genes Dev., 6, 545–556.

  • Bruss V, Lu R, Thomssen R and Gerlich W . (1994). EMBO J. 13, 2273–2279.

  • Heermann KH, Goldmann U, Schwartz W, Seyffarth T, Baumgarten H and Gerlich WH . (1984). J. Virol., 52, 396–402.

  • Hildt E and Hofschneider PH . (1998). Recent Results Cancer Res., 154, 315–329.

  • Hildt E, Munz B, Saher G, Hofschneider PH . (2002). EMBO J., 21, 525–535.

  • Hildt E, Munz B, Saher G, Reifenberg K and Hofschneider PH . (2002). EMBO J., 21, 525–535.

  • Hildt E and Oess S . (1999). J. Exp. Med., 189, 1707–1714.

  • Hildt E, Saher G, Bruss V and Hofschneider PH . (1996). Virology, 225, 235–239.

  • Hildt E, Urban S and Hofschneider PH . (1995). Oncogene, 11, 2055–2066.

  • Kekule AS, Lauer U, Meyer M, Caselmann WH, Hofschneider PH and Koshy R . (1990). Nature, 343, 457–461.

  • Klein NP, Bouchard MJ, Wang LH, Kobarg C and Schneider RJ . (1999). EMBO J., 18, 5019–5027.

  • Klein NP and Schneider RJ . (1997). Mol. Cell Biol., 17, 6427–6436.

  • Lucito R, Schneider RJ . (1992). J. Virol., 66, 983–991.

  • Murakami S, Cheong J, Ohno S, Matsushima K and Kaneko S . (1994). Virology, 199, 243–246.

  • Oess S and Hildt E . (2000). Gene Ther., 7, 750–758.

  • Pleschka S, Wolff T, Ehrhardt C, Hobom G, Planz O, Rapp UR and Ludwig S . (2001). Nat. Cell Biol., 3, 301–305.

  • Sambrook J, Fritsch EF and Maniatis T . (1989). Molecular Cloning: A Laboratory Manual, 2nd edn. Cold Harbour Laboratory Press: Cold Spring Harbour, NY.

    Google Scholar 

  • Schreck R, Grassman R, Fleckenstein B and Baeuerle PA . (1992). J. Virol., 66, 6288–6293.

  • Su F and Schneider RJ . (1996). J. Virol., 70, 4558–4566.

  • Su F, Theodosis CN and Schneider RJ . (2001). J. Virol., 75, 215–225.

  • Twu JS and Schloemer RH . (1987). J. Virol., 61, 3448–3453.

  • Weiss L, Kekule A, Jakubowski U, Burgelt E and Hofschneider PH . (1996). Virology, 216, 214–218.

  • Wollersheim M, Debelka U and Hofschneider PH . (1989). Oncogene, 3, 545–552.

  • Zoulim F, Saputelli J and Seeger C . (1994). J. Virol., 68, 2026–2030.

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Acknowledgements

We thank E Buergelt and S Andric for excellent technical assistance. This work was supported by an RKI-grant to EH.

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Author notes

  1. Lars Stöckl and Andreas Berting: These two authors contributed equally to this work

Authors and Affiliations

  1. Robert Koch-Institut, Berlin, D-13353, Germany

    Lars Stöckl, Beate Malkowski, Ramona Foerste & Eberhard Hildt

  2. Max-Planck-Institut für Biochemie, Martinsried, D-82152, Germany

    Andreas Berting & Peter Hans Hofschneider

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  1. Lars Stöckl
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  2. Andreas Berting
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  3. Beate Malkowski
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  4. Ramona Foerste
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  5. Peter Hans Hofschneider
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  6. Eberhard Hildt
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Correspondence to Eberhard Hildt.

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Stöckl, L., Berting, A., Malkowski, B. et al. Integrity of c-Raf-1/MEK signal transduction cascade is essential for hepatitis B virus gene expression. Oncogene 22, 2604–2610 (2003). https://doi.org/10.1038/sj.onc.1206320

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  • DOI: https://doi.org/10.1038/sj.onc.1206320

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