Activation and Inhibition of Cellular Calcium and Tyrosine Kinase Signaling Pathways Identify Targets of the HBx Protein Involved in Hepatitis B Virus Replication

Bouchard, Michael J.; Puro, Robyn J.; Wang, Lihua; Schneider, Robert J.

doi:10.1128/jvi.77.14.7713-7719.2003

Cited by 119 publications

(115 citation statements)

References 22 publications

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“…It seemed that mitochondrial targeting of HBx triggers at least two important signaling mediators, ROS and calcium. It was previously shown that cytoplasmic calcium released from mitochondria by HBx plays an important role in the regulation of HBV replication [21,26]. Likewise, our data here revealed that the elevated cytoplasmic calcium and subsequent activation of calcium-dependent tyrosine kinase may serve as critical cytoplasmic signals for HBx-mediated COX-2 induction.…”

Section: Discussionsupporting

confidence: 79%

“…Notably, a proline-rich tyrosine kinase, Pyk2, is activated upon increased cytosolic calcium that can be released from HBx-stimulated mitochondria [21,26]. We therefore, investigated whether inhibition of Pyk2 by herbimycin or blocking mitochondrial permeability transition pore, thereby inhibiting cytosolic calcium release, using cyclosporine A (CsA), distort the HBV-mediated COX-2 induction.…”

Section: Mitochondrial Localization Of Hbx Is Necessary But Not Suffimentioning

confidence: 99%

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HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

Lim

Kwon

Cho³

et al. 2009

J Mol Med

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Chronic inflammation can be a major risk factor for cancer development and may contribute to the high worldwide incidence of hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) is known to be an important mediator of inflammatory responses; however, its link to hepatitis B virus (HBV)-mediated inflammatory responses has not been established. Here, we demonstrate that the expression of COX-2 mRNA and protein was significantly elevated in cells transfected by HBV replicon but not in cells transfected by HBV genome lacking the HBx gene. Notably, COX-2 induction was correlated with HBx's ability to increase reactive oxygen species (ROS) levels. Consistently with this, antioxidant treatment and ectopic expression of manganese superoxide dismutase or catalase completely abolished COX-2 induction. Interestingly, a mitochondria localization-defective mutant of HBx (HBx Δ68-117 ) neither increased intracellular ROS levels nor induced COX-2 expression. HBx 68-117 , which encodes only amino acids 68-117 and is sufficient for mitochondria localization, increased ROS levels but did not induce COX-2 expression. Similarly, HBx targeting to the outer membrane of mitochondria (Mito-HBx) increased ROS but also failed to increase COX-2 expression, suggesting that other cytoplasmic signaling pathways are involved in HBx-mediated COX-2 induction. Indeed, inhibition of cytoplasmic calcium signaling by cyclosporine A, blocking mitochondrial permeability transition pore, and herbimycin, and inhibition of calciumdependent tyrosine kinase suppressed HBV-mediated COX-2 induction. Thus, the data indicate that both mitochondrial ROS and cytoplasmic calcium signaling are necessary for the COX-2 induction. Our studies revealed a pathophysiological link between HBV infection and hepatic inflammation, and this chain of events might contribute to early steps in HBV-associated liver carcinogenesis.

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Section: Discussionsupporting

confidence: 79%

Section: Mitochondrial Localization Of Hbx Is Necessary But Not Suffimentioning

confidence: 99%

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

Lim

Kwon

Cho³

et al. 2009

J Mol Med

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“…Recently, in vitro experiments suggest that HBx stimulates HBV replication via its transactivation function (Melegari et al, 2005;Tang et al, 2005). It has been demonstrated that HBx action on viral replication may be dependent to modulation of calcium homeostasis, which provides novel clues for HBx biology (Bouchard et al, 2001(Bouchard et al, , 2003Choi et al, 2005). In addition, HBx interactions with the proteasome complex or DDB1 and HBx activation of Src tyrosine kinases have also been reported to participate in the regulation of HBV replication (Klein et al, 1999;Zhang et al, 2004;Leupin et al, 2005).…”

Section: Hbxmentioning

confidence: 99%

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

et al. 2006

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As discussed in detail in other chapters of this review, chronic hepatitis B (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Most HCCs complicate the evolution of an active or inactive cirrhosis. However, some tumors occur on livers with minimal histological changes; the prevalence of such cases varies from one geographical region to the other, being much higher in the southern half of Africa (around 40% of HCCs) than in Asia, America and Europe, where at least 90% of HCCs are associated with the cirrhosis. This heterogeneity is probably a reflection of different environmental and genetic factors. This review will summarize the current knowledge on the mechanisms involved in HBVrelated liver carcinogenesis. It will show in particular how viruses can be viewed as tools to discover and dissect new cellular pathways involved in cancer development and emphasize the potential synergistic effects between HBV and hepatitis C virus, as well as between viral infections and other environmental factors, such as alcohol.

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“…The conclusion by Tang et al is clearly different from the direct role of HBx in HBV replication reported by the previous studies. (46,47) Zhang et al reported the involvement of proteasome in the stimulatory role of HBx in HBV transcription and replication. (32) Their experiments demonstrated that HBx-assisted enhancement of HBV transcription and replication is through the proteasomedependent pathway since inhibition of cellular proteasome activities enhanced HBV transcription and replication in an HBx-dependent manner.…”

Section: −10mentioning

confidence: 99%

“…(47) HBx was reported to increase the level of calcium in cells, which might be stimulatory for HBV replication because the treatment with drugs like gliotoxin and glibenclimide that augment cytoplasmic calcium ion partially rescued the HBV replication of the X-deficient replicon. They argued that the role of HBx to stimulate HBV replication is not at the level of transcription of pgRNA but at the level of DNA replication.…”

Section: −10mentioning

confidence: 99%

Molecular functions and biological roles of hepatitis B virus x protein

Tang¹,

Oishi²,

Kaneko³

et al. 2006

Cancer Science

266

244

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Chronic infection of hepatitis B virus (HBV) isH epatitis B virus (HBV) infection is a worldwide health problem and is one of the major causes of hepatocellular carcinoma (HCC) in the world. However, new incidences of HBV infection have been dramatically reduced by several prevention programs. The crucial role of HBV in hepatocarcinogenesis is beyond doubt, however, the mechanism by which HBV causes transformation of hepatocytes remains uncertain.(1-3) Hepatitis B virus X protein (HBx) has long been suspected to play a positive role in hepatocarcinogenesis because HCC incidence has been reported in animals infected with mammalian hepadnaviruses. Among these hepadnaviruses, open reading frame-X (X-ORF) is conserved in the genomes. However, hepatocarcinogenesis has not been found in avian infected with avian hepadnaviruses where X-ORF is absent. In addition to the putative contribution of HBx, other oncogenic mechanisms of the HBV-related hepatocarcinogenesis have also been proposed, such as the integration-dependent scenario of HBV DNA in host genomes, (4) and the inflammation-dependent scenario.(5) Since no higher incidence of HCC has been reported in HBV-expressing transgenic mice, (6) host immunological responses to HBV infection (but not HBV proliferation by itself ) might be primarily contributing to the HBV-related hepatocarcinogenesis. HBx, a small protein of 154 amino acids, is a multifunctional regulator that modulates a variety of host processes through directly or indirectly interacting with virus and host factors. (2,3) In this short review, we briefly summarize the life cycle of HBV, expression of HBx, and the molecular functions of HBx. We then focus on the recent progress on the biological roles of HBx in HBV replication and cellular transformation. Expression and functions of HBx. HBV is a prototype of Hepadnaviridae, hepatotropic small DNA viruses, of which hosts are among limited species of water birds, squirrels and primates. The HBV genome is a 3.2-kb circular, partially double-stranded DNA molecule with four overlapping ORFs, PC-C, PS-S, P, and X-ORFs (Fig. 1). (7) Once HBV infection of hepatocytes occurs, its genome is converted to covalently closed circular (CCC) DNA, which serves as the template for transcription by the host RNA polymerase II, generating the 3.5-, 2.4-, 2.1-, and 0.7-kb transcripts under control of four HBV promoters (Cp, PS1p, Sp, and Xp), respectively (Fig. 1). Two HBV enhancers (Enh I and Enh II) positively regulate transcription of the HBV promoters in combination with the transcription factors that bind these promoters.(7-9) HBV replicates by reverse transcription of the viral pregenomic 3.5-kb RNA (pgRNA) using the HBV polymerase that catalyzes RNA-dependent DNA synthesis and DNA-dependent DNA synthesis. (7,10) The reverse transcription of hepadnaviruses is unique among DNA viruses, and the primer of the reverse transcription is a tyrosine residue of an N-terminal domain of Pol that is distinct from reverse transcription of retroviruses. (10)

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Activation and Inhibition of Cellular Calcium and Tyrosine Kinase Signaling Pathways Identify Targets of the HBx Protein Involved in Hepatitis B Virus Replication

Cited by 119 publications

References 22 publications

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

Molecular functions and biological roles of hepatitis B virus x protein

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