Aggregate formation of hepatitis B virus X protein affects cell cycle and apoptosis

Abstract

Our observations show that cells with HBx aggregate undergo growth arrest and apoptosis, whereas control cells without HBx remain in growth and progression into S phase. Our data may provide helpful information to understand the biological effects of HBx aggregates on cells.

Hepatitis B virus HBx protein localized to the nucleus restores HBx-deficient virus replication in HepG2 cells and in vivo in hydrodynamically-injected mice

“…Previous studies addressed the ability of nuclear- and/or cytoplasmic localized HBx to restore HBx-deficient (pHBVΔX) replication (Klein et al, 2001; Leupin et al, 2005) utilizing the cytomegalovirus (CMV) early promoter (Brondyk, 1994) and the SRα promoter (Takebe et al, 1988) that are each anticipated to drive HBx expression to high levels (Table 1). High levels of HBx are reported to aggregate within the cytoplasm and to affect cell cycling (Henkler et al, 2001; Hoare et al, 2001; Song et al, 2003), which may influence the interpretation of those results. Therefore, we began our study by re-creating a panel of plasmid DNAs in which expression of HBx (and its signal-tagged derivatives) was driven from the SV40 early promoter/enhance (Brondyk, 1994) (Fig.…”

“…A comparison with wildtype (pHBV) replication was not included. In addition, that study expressed HBx under control of the strong CMV promoter, shown by others to induce the formation of cytoplasmic granules (Henkler et al, 2001; Hoare et al, 2001; Song et al, 2003). This may provide an explanation for why Cha et al found that HBx restores pHBVΔX to 75% of wildtype (pHBV) replication (versus 100% restoration in our study).…”

Subcellular localization and transcriptional repressor activity of HBx on p21WAF1/Cip1 promoter is regulated by ERK-mediated phosphorylation

“…The HBx protein is a multifunctional viral regulator that modulates transcription, cellular responses to genotoxic stress, protein degradation, and cell signaling pathways [4][5][6]. This ability of HBx to modulate cell survival may be related to viral pathogenicity in acute and chronic HBV infection as well as to the later development of HCC [5,7]. In addition, several studies on HBx transgenic mice have presented evidence that HBx plays a major role in the malignant transformation of liver cells [8,9].…”

“…The HBx gene, which encodes a 154 amino acid protein (molecular weight, 17 kDa) with no sequence homology to any other known protein, is frequently integrated into the cellular genome and expressed in HCC [3]. The HBx protein is a multifunctional viral regulator that modulates transcription, cellular responses to genotoxic stress, protein degradation, and cell signaling pathways [4][5][6]. This ability of HBx to modulate cell survival may be related to viral pathogenicity in acute and chronic HBV infection as well as to the later development of HCC [5,7].…”

The aggregation and inheritance of damaged proteins determines cell fate during mitosis

“…This lengthening of the cell cycle may be due to the time it takes to transport the inclusion body to an area of the cell where it will not interfere with cell division. It is interesting to note that aggregates of hepatitis B virus X protein have been found to lengthen the cell cycle, 20 in contrast to the nonaggregated protein that stimulates proliferation. 21 Therefore, the presence of an aggregate, regardless of the type of protein, may lengthen the cell cycle.…”