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J. Biol. Chem., Vol. 277, Issue 10, 8730-8740, March 8, 2002
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From the Department of Basic Medical Sciences, Purdue University,
West Lafayette, Indiana 47907-1246
Hepatitis B virus (HBV) X protein (pX) is
implicated in hepatocarcinogenesis of chronically infected HBV
patients. To understand mechanism(s) of pX-mediated cellular
transformation, we employed two tetracycline-regulated, pX-expressing
cell lines, constructed in AML12 immortalized hepatocytes: one a
differentiated (3pX-1) and the other a de-differentiated (4pX-1)
hepatocyte cell line. Only 3pX-1 cells undergo pX-mediated
transformation, via sustained Ras-Raf-mitogen-activated protein
kinase pathway activation. pX-nontransforming 4pX-1 cells display
sustained, pX-dependent JNK pathway activation. To
understand how pX mediates different growth characteristics in 3pX-1
and 4pX-1 cells, we report, herein, comparative cell cycle analyses.
pX-transforming 3pX-1 cells display pX-dependent G1, S, and G2/M progression evidenced by
cyclin D1, A, and B1 induction, and Cdc2 kinase
activation. pX-nontransforming 4pX-1 cells display
pX-dependent G1 and S phase entry, followed by
S phase pause and absence of Cdc2 kinase activation. Interestingly, 4pX-1 cells exhibit selective pX-induced expression of
cyclin-dependent kinase inhibitor p21Cip1,
tumor suppressor p19ARF, and proapoptotic genes
bax and IGFBP-3. Despite the pX-mediated induction of growth arrest and apoptotic genes and the absence of
pX-dependent Cdc2 activation, 4pX-1 cells do not undergo
pX-dependent G2/M arrest or apoptosis.
Nocodazole-treated, G2/M-arrested 4pX-1 cells exhibit
pX-dependent formation of multinucleated cells, similar to
human T-cell lymphotropic virus type I Tax-expressing cells. We
propose that in 4pX-1 cells, pX deregulates the G2/M checkpoint, thus rescuing cells from pX-mediated apoptosis.
Hepatitis B Virus X Protein Differentially Regulates Cell Cycle
Progression in X-transforming Versus Nontransforming
Hepatocyte (AML12) Cell Lines*
*
This work was supported by National Institutes of Health
Grant DK44533 (to O. M. A.).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: Dept. of Basic Medical
Sciences, Purdue University, West Lafayette, IN 47907-1246. Tel.:
765-494-8131; Fax: 765-494-1781; E-mail: oma@vet.purdue.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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