Hepatitis B virus X protein: a multifunctional viral regulator

Murakami, Seishi

doi:10.1007/s005350170027

Cited by 302 publications

(257 citation statements)

References 98 publications

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“…(Figure 6) Furthermore, by losing the proapoptotic ability, the mutant HBx enhanced the transforming ability of ras and myc (Tu et al, 2001). The abrogation of p53-mediated apoptosis by HBx (also reviewed by Arbuthnot et al, 2000;Bergsland, 2001;Murakami, 2001) may provide a selective clonal advantage for preneoplastic or neoplastic hepatocytes and contribute to hepatocellular carcinogenesis. Molecular epidemiological studies also support the hypothesis that mutant HBx integrated in HCC is positively associated with TP53 249 ser mutations.…”

Section: Tp53 Mutations and Hcc Sp Hussain Et Almentioning

confidence: 99%

TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer

et al. 2007

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Section: Tp53 Mutations and Hcc Sp Hussain Et Almentioning

confidence: 99%

TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer

et al. 2007

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“…A wide variety of cis-elements, designated as xenobiotic responsive elements, have been documented to be responsive to HBx, including binding sites for AP-1, AP-2, NF-kB, SRF, c/EBP, Ets, ATF1 and CREB. 25,31,32 Replication of the HBx-deficient HBV replicon in HepG2 cells was reduced by threefold compared with wild-type HBV, suggesting that HBx plays a stimulatory role in HBV replication. 33 The information on HBx protein continues to grow, although many of the roles and functions of HBx remain controversial.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

Wang

Mao

et al. 2010

Cell Mol Immunol

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Viral RNAs produced during viral infection are recognized by the cytoplasmic RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). A central adapter protein downstream of RIG-I and MDA5 is the mitochondrial membrane protein virus-induced signaling adaptor (VISA), which mediates the induction of type I interferons (IFNs) through the activation of transcription factors such as nuclear factor-kappaB (NF-kB) and IFN-regulatory factor-3 (IRF3). Here we found that hepatitis B virus (HBV)-encoded X protein (HBx) acts as an inhibitor of virus-triggered IRF3 activation and IFN-b induction. Reporter and plaque assays indicate that HBx inhibits signaling by components upstream but not downstream of VISA. Immunoprecipitation experiments indicate that HBx interacts with VISA and disrupts the association of VISA with its upstream and downstream components. These findings suggest that HBx acts as a suppressor of virus-triggered induction of type I IFNs, which explains the observation that HBV causes transient and chronic infection in hepatocytes but fails to activate the pattern recognition receptor-mediated IFN induction pathways.

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“…HBV has a circular, partially double-stranded DNA genome that consists of four overlapping open reading frames encoding DNA polymerase, HBV surface protein, HBV core protein and a regulatory X protein, HBx. Among these, HBx has been the focus of much attention because it is strongly implicated in hepatocarcinogenesis (Murakami 2001;Zhang et al, 2006). Forced expression of HBx protein enhanced the survival and proliferative potential of liver cells, whereas knockdown of HBx gene reduces the tumorigenicity of HCC cells (Yun et al, 2002;Chan and Ng, 2006).…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

et al. 2008

Oncogene

144

129

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Expression level of metastasis-associated protein 1 (MTA1) is closely related to tumor growth and metastasis in various cancers. Although increased expression level of MTA1 was observed in hepatocellular carcinoma (HCC), role of MTA1 complex containing histone deacetylase (HDAC) in hepatitis B virus (HBV)-associated hepatocarcinogenesis has not been studied. Here, we demonstrated that HBx strongly induced the expression of MTA1 and HDAC1 genes at transcription level. MTA1 and HDAC1/2 physically associated with hypoxia-inducible factor-1a (HIF-1a) in vivo in the presence of HBx, which was abolished by knockdown of MTA1 by short interfering RNA (siRNA). HBx induced deacetylation of the oxygen-dependent degradation domain of HIF-1a, which was accompanied with dissociation of prolyl hydroxylases and von Hippel-Lindau tumor suppressor from HIF-1a. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1a. Further, we observed that protein levels of MTA1 and HDAC1 were increased in the liver of HBxtransgenic mice. Also, there was a higher expression of HDAC1 in HCC than in the adjacent non-tumorous cirrhotic nodules in 10 out of 12 human HBV-associated HCC specimens. Together, our data indicate a positive cross talk between HBx and the MTA1/HDAC complex in stabilizing HIF-1a, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.

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Hepatitis B virus X protein: a multifunctional viral regulator

Cited by 302 publications

References 98 publications

TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer

TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

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