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J. Virol. doi:10.1128/JVI.00661-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The mitogenic function of Hepatitis B virus X protein resides within amino acids 51-140 and is modulated by N- and C-terminal regulatory regions

Department of Basic Medical Sciences, Purdue University, West Lafayette, IN USA

^* To whom correspondence should be addressed. Email: andrisao{at}purdue.edu.

	Abstract

The Hepatitis B virus X protein (pX) is implicated in hepatocarcinogenesis by an unknown mechanism. pX variants encoded by HBV genomes found integrated in genomic DNA from liver tumors of patients with hepatocellular carcinoma (HCC), generally lack amino acids 134-154. Since deregulation of mitogenic pathways is linked to oncogenic transformation, herein we define the pX region required for mitogenic pathway activation. A series of pX deletions was used to construct tetracycline-regulated pX-expressing cell lines. The activation of the mitogenic pathways by these pX deletions expressed in the constructed cell lines was measured by transient transreporter assays, effects on endogenous cyclin A expression, and apoptosis. Conditional expression of pX_51-140 in AML12 clone 4 cell line activates the mitogenic pathways, induces endogenous cyclin A expression and sensitizes cells to apoptosis, similar to WT pX. By contrast, pX_1-115 is inactive, supporting amino acids 116-140 are required for mitogenic pathway activation. Moreover, this pX deletion analysis demonstrates that WT pX function is modulated by two regions spanning amino acids 1-78 and 141-154. The N-terminal X_1-78, expressed via a retroviral vector in WT pX-expressing 4pX-1 cells, co-immunoprecipitates with WT pX, indicating this pX region participates in protein-protein interactions leading to pX oligomerization. Interestingly, pX_1-78 interferes with WT pX in mediating mitogenic pathway activation, endogenous gene expression, and apoptosis. The C-terminal pX region spanning amino acids 141-154 decreases pX stability, determined by pulse-chase studies of WT pX and pX_1-140, suggesting that increased stability of naturally occurring pX variants lacking amino acids 134-154 may play a role in HCC development.