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J. Biol. Chem., Vol. 276, Issue 11, 8328-8340, March 16, 2001
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From the The X protein from a chronic strain of hepatitis
B virus (HBx) was determined to inhibit Fas-mediated apoptosis and
promote cell survival. Fas-mediated apoptosis is the major cause of
hepatocyte damage during liver disease. Experiments demonstrated that
cell death caused by anti-Fas antibodies was blocked by the expression of HBx in human primary hepatocytes and mouse embryo fibroblasts. This
effect was also observed in mouse erythroleukemia cells that lacked
p53, indicating that protection against Fas-mediated apoptosis was
independent of p53. Components of the signal transduction pathways
involved in this protection were studied. The SAPK/JNK pathway has
previously been suggested to be a survival pathway for some cells
undergoing Fas-mediated apoptosis, and kinase assays showed that SAPK
activity was highly up-regulated in cells expressing the HBx protein.
Normal mouse fibroblasts expressing HBx were protected from death,
whereas identical fibroblasts lacking the SEK1 component
from the SAPK pathway succumbed to Fas-mediated apoptosis, whether HBx
was present or not. Assays showed that caspase 3 and 8 activities and
the release of cytochrome c from mitochondria were
inhibited, in the presence of HBx, following stimulation with anti-Fas
antibodies. Coprecipitation and confocal immunofluorescence microscopy
experiments demonstrated that HBx localizes with a cytoplasmic complex
containing MEKK1, SEK1, SAPK, and 14-3-3 proteins. Finally, mutational
analysis of HBx demonstrated that a potential binding region for 14-3-3 proteins was essential for induction of SAPK/JNK activity and
protection from Fas-mediated apoptosis.
X Protein of Hepatitis B Virus Inhibits
Fas-mediated Apoptosis and Is Associated with Up-regulation of the
SAPK/JNK Pathway*
,,§,§¶, and§¶
Department of Medical Biophysics, University
of Toronto, Toronto, Ontario M5G 2M9, the § Ontario Cancer
Institute, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, and
¶ Amgen Research Institute,
Toronto, Ontario M5G 2C1, Canada
*
This work was supported by Medical Research Council of
Canada Operating Grant MT-10638 and an Ontario Graduate Scholarship (to
J. D.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Amgen Research
Institute, 620 University Ave., Suite 706, Toronto, Ontario M5G 2C1,
Canada. Tel.: 416-204-2280; Fax: 416-204-2278; E-mail:
crichard@amgen.com.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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