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Journal of Virology, May 2009, p. 4718-4731, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02590-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Hepatitis B Virus X Protein Modulates Apoptosis in Primary Rat Hepatocytes by Regulating both NF-{kappa}B and the Mitochondrial Permeability Transition Pore{triangledown}

Amy J. Clippinger,1 Tricia L. Gearhart,1 and Michael J. Bouchard2*

Graduate Program in Molecular and Cellular Biology and Genetics,1 Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 191022

Received 15 December 2008/ Accepted 27 February 2009

The hepatitis B virus (HBV) X protein (HBx) is a multifunctional protein that regulates numerous cellular signal transduction pathways, including those that modulate apoptosis. However, different HBx-dependent effects on apoptosis have been reported; these differences are likely the consequence of the exact conditions and cell types used in a study. Many of the previously reported studies that analyzed HBx regulation of apoptosis were conducted in immortalized or transformed cells, and the alterations that have transformed or immortalized these cells likely impact apoptotic pathways. We examined the effects of HBx on apoptotic pathways in cultured primary rat hepatocytes, a biologically relevant system that mimics normal hepatocytes in the liver. We analyzed the effects of HBx on apoptosis both when HBx was expressed in the absence of other HBV proteins and in the context of HBV replication. HBx stimulation of NF-{kappa}B inhibited the activation of apoptotic pathways in cultured primary rat hepatocytes. However, when HBx-induced activation of NF-{kappa}B was blocked, HBx stimulated apoptosis; blocking the activity of the mitochondrial permeability transition pore inhibited HBx activation of apoptosis. These results suggest that HBx can be either proapoptotic or antiapoptotic in hepatocytes, depending on the status of NF-{kappa}B, and confirm previous studies that link some HBx activities to modulation of the mitochondrial permeability transition pore. Overall, our studies define apoptotic pathways that are regulated by HBx in cultured primary hepatocytes and provide potential mechanisms for the development of HBV-associated liver cancer.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA 19102. Phone: (215) 762-1898. Fax: (215) 762-4452. E-mail: michael.bouchard{at}drexelmed.edu

{triangledown} Published ahead of print on 11 March 2009.

Journal of Virology, May 2009, p. 4718-4731, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02590-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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