Genetic dissection of naturally occurring basal core promoter mutations of hepatitis B virus reveals a silent phenotype in the overlapping X gene

Hussain, Zahid; Jung, Hyeon Sik; Ryu, Dong Kyun; Ryu, Wang Shick

doi:10.1099/vir.0.010421-0

Cited by 13 publications

(11 citation statements)

References 32 publications

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“…further explored the potential role of HBx alteration by overlapping BCP mutations on viral genome replication. Their results indicated that the A1762T and G1764A double mutation in the BCP, but not in the overlapping X gene, is responsible for the enhanced viral genome replication observed for BCP mutants …”

Section: Discussionmentioning

confidence: 99%

HBx mutations promote hepatoma cell migration through the Wnt/β‐catenin signaling pathway

et al. 2016

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HBx mutations (T1753V, A1762T, G1764A, and T1768A) are frequently observed in hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC). Aberrant activation of the Wnt/β‐catenin signaling pathway is involved in the development of HCC. However, activation of the Wnt/β‐catenin signaling pathway by HBx mutants has not been studied in hepatoma cells or HBV‐associated HCC samples. In this study, we examined the effects of HBx mutants on the migration and proliferation of HCC cells and evaluated the activation of Wnt/β‐catenin signaling in HBx‐transfected HCC cells and HBV‐related HCC tissues. We found that HBx mutants (T, A, TA, and Combo) promoted the migration and proliferation of hepatoma cells. The HBx Combo mutant potentiated TOP‐luc activity and increased nuclear translocation of β‐catenin. Moreover, the HBx Combo mutant increased and stabilized β‐catenin levels through inactivation of glycogen synthase kinase‐3β, resulting in upregulation of downstream target genes such as c‐Myc,CTGF, and WISP2. Enhanced activation of Wnt/β‐catenin was found in HCC tissues with HBx TA and Combo mutations. Knockdown of β‐catenin effectively abrogated cell migration and proliferation stimulated by the HBx TA and Combo mutants. Our results indicate that HBx mutants, especially the Combo mutant, allow constitutive activation of the Wnt signaling pathway and may play a pivotal role in HBV‐associated hepatocarcinogenesis.

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Section: Discussionmentioning

confidence: 99%

HBx mutations promote hepatoma cell migration through the Wnt/β‐catenin signaling pathway

et al. 2016

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“…domains of the polymerase overlaps completely with the ORF S that encodes HBV surface proteins (Michel and Tiollais, 1987). Moreover, viral sequences HBV X gene overlaps the ORF C region, and mutations in both ORF X and ORF C often occur together (Hussain et al, 2009). The four protein-coding regions are shown between the inner and outer circles (Seeger and Mason, 2000).…”

Section: * General Features Of Hepatitis B Virusmentioning

confidence: 99%

“…The C-terminal domain of the HBV X gene overlaps the BCP region, and mutations in both HBx and BCP often occur together (Park and Chung, 2007;Hussain et al, 2009). Thus , the BCP overlaps with the X region of the HBV genome, and mutations in the amino acid sequence at positions 130 and 131 (at codon 130 [AAG g ATG] and 131 [GTC g ATC]).…”

Section: Secondary Mutations In Hbv X Gene and Risk Of Hccmentioning

confidence: 99%

Hepatitis B Virus Gene Mutations and Hepatocarcinogenesis

Liang¹,

Chen²,

Tang³

2013

Asian Pacific Journal of Cancer Prevention

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“…Such a property is useful for the screen of antiviral agents and generation of virus particles for infection experiments, but rather undesirable when comparing biological properties of HBV genetic variants. The minimum HBV genome for efficient replication under the endogenous regulatory elements is 1.3mer with the core promoter (which drives transcription of the 3.5-kb RNAs) located at the 5′ end (Guidotti et al, 1995; Hussain et al 2009; Zhang et al, 2015). Longer versions such as 1.5mer (Garcia et al, 2009) and tandem dimer also work.…”

Section: Discussionmentioning

confidence: 99%

Two-way molecular ligation for efficient conversion of monomeric hepatitis B virus DNA constructs into tandem dimers

Zong

Qin

Jia

et al. 2016

Journal of Virological Methods

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Replication of the 3.2-kb hepatitis B virus (HBV) genome is driven by the covalently closed circular (ccc) DNA in the nucleus, from which four classes of co-terminal RNAs are transcribed. Genome replication requires just the 3.5-kb pregenomic RNA, which is terminally redundant. Cloning the full-length HBV genome into a vector disrupts its continuity, thus preventing genome replication at the step of pregenomic RNA transcription. This can be overcome by converting the monomeric construct into a tandem dimer, yet the need to ligate two molecules of the HBV genome with vector DNA makes it inefficient and even unsuccessful. To overcome this problem we partially digested the monomeric construct with the unique restriction enzyme used for cloning, and dephosphorylated the linearized monomer before its ligation with another copy of the HBV genome. Alternatively, the monomer was linearized at another unique restriction site inside the HBV genome, followed by its dephosphorylation and ligation with another copy of the HBV genome linearized at the same site. These approaches of two-way molecular ligation greatly improved the efficiency of dimer formation with about 50% of the bacterial colonies screened harboring tandem dimers.

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Genetic dissection of naturally occurring basal core promoter mutations of hepatitis B virus reveals a silent phenotype in the overlapping X gene

Cited by 13 publications

References 32 publications

HBx mutations promote hepatoma cell migration through the Wnt/β‐catenin signaling pathway

HBx mutations promote hepatoma cell migration through the Wnt/β‐catenin signaling pathway

Hepatitis B Virus Gene Mutations and Hepatocarcinogenesis

Two-way molecular ligation for efficient conversion of monomeric hepatitis B virus DNA constructs into tandem dimers

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