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J. Biol. Chem., Vol. 276, Issue 20, 16969-16977, May 18, 2001
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From the Liver Cell Signal Transduction Research Unit,
The hepatitis B virus-X (HBx) protein is known as
a multifunctional protein that not only coactivates transcription of
viral and cellular genes but coordinates the balance between
proliferation and programmed cell death, by inducing or blocking
apoptosis. In this study the role of the HBx protein in activation of
phosphatidylinositol 3-kinase (PI3K) was investigated as a
possible cause of anti-apoptosis in liver cells. HBx relieved serum
deprivation-induced and pro-apoptic stimuli-induced apoptosis in Chang
liver (CHL) cells. Treatment with
1-D-3-deoxy-3-fluoro-myo-inositol, an
antagonist to PI3K, which blocks the formation of 3'-phosphorylated
phosphatidyl inositol in CHL cells transformed by HBx
(CHL-X) but not normal Chang liver (CHL) cells, showed a marked loss of
viability with evidence of apoptosis. Similarly, treatment with
wortmannin, an inhibitor of PI3K, stimulated apoptosis in
HBx-transformed CHL cells but not in normal cells,
confirming that HBx blocks apoptosis through the PI3K pathway. The
serine 47 threonine kinase, Akt, one of the downstream effectors of
PI3K-dependent survival signaling was 2-fold higher in
HBx-transformed CHL (CHL-X) cells than CHL cells.
Phosphorylation of Akt at serine 473 and Bad at serine 136 were induced
by HBx, which were specifically blocked by wortmannin and dominant
negative mutants of Akt and Bad, respectively. We also demonstrated
that HBx inhibits caspase 3 activity and HBx down-regulation of caspase
3 activity was blocked by the PI3K inhibitor. Regions required for PI3K
phosphorylation on the HBx protein overlap with the known
transactivation domains. HBx blocks apoptosis induced by serum
withdrawal in CHL cells in a p53-independent manner. The results
indicate that, unlike other DNA tumor viruses that block apoptosis by
inactivating p53, the hepatitis B virus achieves protection from
apoptotic death through a HBx-PI3K-Akt-Bad pathway and by inactivating
caspase 3 activity that is at least partially p53-independent in liver
cells. Moreover, these data suggest that modulation of the PI3K
activity may represent a potential therapeutic strategy to counteract
the occurrence of apoptosis in human hepatocellular carcinoma.
The Hepatitis B Virus-X Protein Activates a Phosphatidylinositol
3-Kinase-dependent Survival Signaling Cascade*
, and Animal Cell and Medical Glycobiology Research Unit,
Bioscience Research Division, Korea Research Institute of Bioscience
and Biotechnology, P. O. Box 115, Yusong, Taejon 305-600, Korea
*
This work was supported by grants from the Korean Science
and Engineering Foundation (Science Research Center Fund) and Korea Ministry of Science and Technology (grant NBM0080031).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.
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