Pro-apoptotic effect of the hepatitis B virus X gene

Pollicino, Teresa; Terradillos, Olivier; Lecœur, Hervé; Gougeon, M.; Ma, Bi

doi:10.1016/s0753-3322(99)80003-1

Cited by 51 publications

(47 citation statements)

References 26 publications

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“…In other transgenic models, HBx expression has no obvious pathological e ect, but it sensitizes liver cells to carcinogenic treatments and it co-operates with c-myc in accelerating liver carcinogenesis (Slagle et al, 1996;Terradillos et al, 1997). Importantly, a number of studies in di erent experimental systems have recently provided evidence for HBx's properties in apoptosis (Chirillo et al, 1997;Kim et al, 1998;Oguey et al, 1996;Pollicino et al, 1998;Su and Schneider, 1997;Terradillos et al, 1998). By contrast in other studies, HBx has been reported to inhibit apoptosis induced by p53 or by TGF-û (Elmore et al, 1997;Shih et al, 2000;Wang et al, 1995), and HBx induction of NF-kB has been shown to promote cell survival (Pan et al, 2001;Su et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver

et al. 2002

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The role of the hepatitis B virus protein HBx in liver cell proliferation and apoptosis remains controversial. Using a transgenic mouse model, we have recently shown that HBx stimulates the apoptotic turnover of hepatocytes, independently of p53. In this paper, we tested whether the proapoptotic function of HBx can interfere with Bcl-2 during hepatic apoptosis in vivo. HBx transgenic mice were crossed with PK-hBcl-2 mice that are protected against Fas killing by constitutive overexpression of Bcl-2 in hepatocytes. In a lethal challenge with Fas antibodies, HBx expressed at low levels restored sensitivity to Fas-mediated apoptosis and fulminant hepatic failure in mice overexpressing Bcl-2. Furthermore, cytochrome c release from mitochondria and caspase 3 activation were restored to normal levels in HBx/Bcl-2 mice during transduction of the Fas signal. Thus, the proapoptotic activity of HBx overcomes or bypasses the inhibitory e ect of Bcl-2 against Fas cytotoxicity. This e ect was not apparently mediated through downregulation of the PK-hBcl-2 transgene or via delocalization of the Bcl-2 protein, and a direct interaction of HBx with Bcl-2, Bcl-X L or Bax could not be evidenced in yeast two-hybrid assays. We further show that apoptosis induced by ectopic expression of HBx is associated with mitochondrial membrane alterations and caspase 3 activation. Our data indicate that the dominant function of HBx upon Bcl-2-regulated control of apoptosis might play an important role in the pathogenesis of chronic hepatitis B.

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Section: Introductionmentioning

confidence: 99%

The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver

et al. 2002

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“…HBx can sensitize liver cells to cell death by various insults, including tumor necrosis factor-α (TNF-α) and growth factor deprivation (10,11). HBx induces mitochondria aggregation, loss of mitochondrial membrane potential, and cytochrome c release, indicating that HBx may act through mitochondria to induce cell death (12)(13)(14)(15).…”

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confidence: 99%

“…HBx induces mitochondria aggregation, loss of mitochondrial membrane potential, and cytochrome c release, indicating that HBx may act through mitochondria to induce cell death (12)(13)(14)(15). Apoptosis and necrosis are also early events of liver pathogenesis in HBx transgenic mice and may lead to development of cirrhosis and HCC (9,10,12). Whereas these reports suggest a hepatotoxic function for HBx, the cellular targets and signaling pathways that HBx exploits to promote cell death and the development of HCC remain unclear.…”

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confidence: 99%

“…Whereas these reports suggest a hepatotoxic function for HBx, the cellular targets and signaling pathways that HBx exploits to promote cell death and the development of HCC remain unclear. It has been hypothesized that chronic hepatocyte cell death causes cycles of inflammatory cytokine release, local liver damage, and compensatory regeneration, leading to the continual acquisition of oncogenic mutations and the development of HCC (10,16). Therefore, identification of cellular targets and pathways that mediate HBxinduced cell death is critical for treating HBV-related liver disease.…”

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confidence: 99%

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Hepatitis B virus X protein targets the Bcl-2 protein CED-9 to induce intracellular Ca ²⁺ increase and cell death in Caenorhabditis elegans

Geng

Harry

Zhou

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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HBx is a multifunctional hepatitis B virus (HBV) protein that is crucial for HBV infection and pathogenesis and a contributing cause of hepatocyte carcinogenesis. However, the host targets and mechanisms of action of HBx are poorly characterized. We show here that expression of HBx in Caenorhabditis elegans induces both necrotic and apoptotic cell death, mimicking an early event of liver infection by HBV. Genetic and biochemical analyses indicate that HBx interacts directly with the B-cell lymphoma 2 (Bcl-2) homolog CED-9 (cell death abnormal) through a Bcl-2 homology 3 (BH3)-like motif to trigger both cytosolic Ca 2+ increase and cell death. Importantly, Bcl-2 can substitute for CED-9 in mediating HBx-induced cell killing in C. elegans, suggesting that CED-9 and Bcl-2 are conserved cellular targets of HBx. A genetic suppressor screen of HBx-induced cell death has produced many mutations, including mutations in key regulators from both apoptosis and necrosis pathways, indicating that this screen can identify new apoptosis and necrosis genes. Our results suggest that C. elegans could serve as an animal model for identifying crucial host factors and signaling pathways of HBx and aid in development of strategies to treat HBV-induced liver disorders.

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“…HBx has been shown to affect a number of cellular processes (reviewed in reference 1). Among the best documented functions, transcriptional transactivation of several cellular and viral promoters (reviewed in references 7, 34, and 48) and stimulation of the apoptotic pathway (4,8,19,31,42) have received a wide range of experimental support. HBx has also been reported to inhibit the transactivation function and cause cytoplasmic sequestration of p53 (13,44,46).…”

mentioning

confidence: 99%

DDB2 Induces Nuclear Accumulation of the Hepatitis B Virus X Protein Independently of Binding to DDB1

Nag

Datta²,

Yoo

et al. 2001

J Virol

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The hepatitis B virus (HBV) X protein (HBx) is critical for the life cycle of the virus. HBx associates with several host cell proteins including the DDB1 subunit of the damaged-DNA binding protein DDB. Recent studies on the X protein encoded by the woodchuck hepadnavirus have provided correlative evidence indicating that the interaction with DDB1 is important for establishment of infection by the virus. In addition, the interaction with DDB1 has been implicated in the nuclear localization of HBx. Because the DDB2 subunit of DDB is required for the nuclear accumulation of DDB1, we investigated the role of DDB2 in the nuclear accumulation of HBx. Here we show that expression of DDB2 increases the nuclear levels of HBx. Several C-terminal deletion mutants of DDB2 that fail to bind DDB1 are able to associate with HBx, suggesting that DDB2 may associate with HBx independently of binding to DDB1. We also show that DDB2 enhances the nuclear accumulation of HBx independently of binding to DDB1, since a mutant that does not bind DDB1 is able to enhance the nuclear accumulation of HBx. HBV infection is associated with liver pathogenesis. We show that the nuclear levels of DDB1 and DDB2 are tightly regulated in hepatocytes. Studies with regenerating mouse liver indicate that during late G 1 phase the nuclear levels of both subunits of DDB are transiently increased, followed by a sharp decrease in S phase. Taken together, these results suggest that DDB1 and DDB2 would participate in the nuclear functions of HBx effectively only during the late-G 1 phase of the cell cycle.Chronic infection with hepatitis B virus (HBV) is believed to be one of the key risk factors for the development of hepatocellular carcinoma (2,11,26,33,43). Despite the existence of successful vaccination programs, human HBV continues to be a major health problem, affecting around 350 million people worldwide (16). HBV belongs to the hepadnavirus family, which includes rodent viruses, such as woodchuck hepatitis virus (WHV) and ground squirrel hepatitis virus, and the distantly related duck hepatitis virus. The X gene of mammalian HBV encodes a small (17-kDa) multifunctional protein named HBx, which shares no similarity with any other known viral or cellular protein (25). HBx has been shown to affect a number of cellular processes (reviewed in reference 1). Among the best documented functions, transcriptional transactivation of several cellular and viral promoters (reviewed in references 7, 34, and 48) and stimulation of the apoptotic pathway (4,8,19,31,42) have received a wide range of experimental support. HBx has also been reported to inhibit the transactivation function and cause cytoplasmic sequestration of p53 (13,44,46).Previous studies have shown that HBx binds to the DDB1 subunit (125 kDa) of UV-damaged DNA binding protein (DDB) (3,20,40). DDB has been implicated in DNA repair (10,14,15,17,18,28,30,32,45). Mutational analysis of HBx has demonstrated a partial correlation between the reduction of repair activity in cells expressing HBx and the abi...

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Pro-apoptotic effect of the hepatitis B virus X gene

Cited by 51 publications

References 26 publications

The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver

The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver

Hepatitis B virus X protein targets the Bcl-2 protein CED-9 to induce intracellular Ca ²⁺ increase and cell death in Caenorhabditis elegans

DDB2 Induces Nuclear Accumulation of the Hepatitis B Virus X Protein Independently of Binding to DDB1

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Pro-apoptotic effect of the hepatitis B virus X gene

Cited by 51 publications

References 26 publications

The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver

The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver

Hepatitis B virus X protein targets the Bcl-2 protein CED-9 to induce intracellular Ca 2+ increase and cell death in Caenorhabditis elegans

DDB2 Induces Nuclear Accumulation of the Hepatitis B Virus X Protein Independently of Binding to DDB1

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Hepatitis B virus X protein targets the Bcl-2 protein CED-9 to induce intracellular Ca ²⁺ increase and cell death in Caenorhabditis elegans