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Journal of Virology, November 2001, p. 10348-10358, Vol. 75, No. 21
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.21.10348-10358.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Sustained Activation of Mitogen-Activated Protein Kinases and Activator Protein 1 by the Hepatitis B Virus X Protein in Mouse Hepatocytes In Vivo

Ruchika Nijhara,1 Siddhartha S. Jana,1 Shyamal K. Goswami,2 Ajay Rana,3 Subeer S. Majumdar,4 Vijay Kumar,5 and Debi P. Sarkar1,*

Department of Biochemistry, University of Delhi South Campus, New Delhi-110021,1 and School of Life Sciences, Jawaharlal Nehru University,2 National Institute of Immunology, Aruna Asaf Ali Marg,4 and Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg,5 New Delhi-110067, India, and Division of Molecular Cardiology, Texas A&M University System Health Science Center, Temple, Texas 765043

Received 26 March 2001/Accepted 30 July 2001

Transcriptional activation of diverse cellular genes by the X protein (HBx) of hepatitis B virus (HBV) has been suggested as one of the mechanisms for HBV-associated hepatocellular carcinoma. However, such functions of HBx have been studied using transformed cells in culture and have not been examined in the normal adult hepatocytes, a natural host of HBV. Using an efficient hepatocyte-specific virus-based gene delivery system developed in our laboratory earlier, we studied the HBx action in vivo. We demonstrate that following virosome-mediated delivery of HBx DNA, a large population (>50%) of hepatocytes express the HBx protein in a dose-dependent manner, which induces a significant increase in the activity of extracellular signal-regulated kinases (ERKs) in the livers of HBx-transfected mice. Inhibition of HBx-induced ERK activation following intravenous administration of PD98059, a mitogen-activated protein kinase kinase kinase (MEK) inhibitor, confirmed the requirement for MEK in the activation of ERKs by HBx. Induction of ERK activity by HBx was sustained for up to 30 days. Interestingly, sustained activation of c-Jun N-terminal kinases (JNKs) for up to 30 days was also noted. Such constitutive ERK and JNK activation as a consequence of continued HBx expression also led to sustained stimulation of further downstream events, such as increased levels of c-Jun and c-Fos proteins along with the persistent induction of activator protein 1 binding activity. Taken together, our data suggest a critical role of these molecules in HBx-mediated cell transformation.

* Corresponding author. Mailing address: Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi 110021, India. Phone: 91-11-6881967. Fax: 91-11-6885270 or 91-11-6886427. E-mail: sarkar{at}del3.vsnl.net.in or dpsarkar{at}hotmail.com.

Journal of Virology, November 2001, p. 10348-10358, Vol. 75, No. 21
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.21.10348-10358.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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