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Chong RHH, Khakpoor A, Tan TMC, Lim SG, Lee GH. Liver-Derived Cell Transfection Model Efficacy for HBV Genotype B Replication/Transcription Is Determined by Complex Host Transcription Factor Network. Viruses 2021; 13:v13030524. [PMID: 33810128 PMCID: PMC8005026 DOI: 10.3390/v13030524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/16/2021] [Accepted: 03/18/2021] [Indexed: 11/20/2022] Open
Abstract
Background: Interaction between host transcription factors (TFs) and the viral genome is fundamental for hepatitis B virus (HBV) gene expression regulation. Additionally, the distinct interaction of the TFs’ network with the HBV genome determines the regulatory effect outcome. Hence, different HBV genotypes and their variants may display different viral replication/transcription regulation. Due to the lack of an efficient infection model suitable for all HBV genotypes, the hepatoma cell transfection model is primarily used in studies involving non-D HBV genotypes and variants. Methods: We explored the transcriptome profile of host TFs with a regulatory effect on HBV in eight liver-derived cell lines in comparison with primary human hepatocytes (PHH). We further analyzed the suitability of these models in supporting HBV genotype B replication/transcription. Results: Among studied models, HC-04, as a result of the close similarity of TFs transcriptome profile to PHH and the interaction of specific TFs including HNF4α and PPARα, showed the highest efficiency in regard to viral replication and antigen production. The absence of TFs expression in L02 transfection model resulted in its inefficiency in HBV replication/transcription. Conclusion: These observations help to better design studies on regulatory mechanisms involving non-D HBV genotypes and variants’ gene expression and the development of more efficient therapeutical approaches.
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Affiliation(s)
- Roxanne Hui-Heng Chong
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore; (R.H.-H.C.); (A.K.); (S.-G.L.)
| | - Atefeh Khakpoor
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore; (R.H.-H.C.); (A.K.); (S.-G.L.)
| | - Theresa May-Chin Tan
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore;
| | - Seng-Gee Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore; (R.H.-H.C.); (A.K.); (S.-G.L.)
| | - Guan-Huei Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore; (R.H.-H.C.); (A.K.); (S.-G.L.)
- Department of Medicine, National University Hospital, Singapore 119074, Singapore
- Correspondence: ; Tel.: +65-90181914
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Xia Y, Guo H. Hepatitis B virus cccDNA: Formation, regulation and therapeutic potential. Antiviral Res 2020; 180:104824. [PMID: 32450266 PMCID: PMC7387223 DOI: 10.1016/j.antiviral.2020.104824] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/03/2020] [Accepted: 05/18/2020] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection remains a major public health concern worldwide with about 257 million individuals chronically infected. Current therapies can effectively control HBV replication and slow down disease progress, but cannot cure HBV infection. Upon infection, HBV establishes a pool of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. The cccDNA exists as a minichromosome and resists to antivirals, thus a therapeutic eradication of cccDNA from the infected cells remains unattainable. In this review, we summarize the state of knowledge on the mechanisms underlying cccDNA formation and regulation, and discuss the possible strategies that may contribute to the eradication of HBV through targeting cccDNA.
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Affiliation(s)
- Yuchen Xia
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
| | - Haitao Guo
- UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
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Tian H, He Z. miR-200c targets nuclear factor IA to suppress HBV replication and gene expression via repressing HBV Enhancer I activity. Biomed Pharmacother 2018; 99:774-780. [PMID: 29710475 DOI: 10.1016/j.biopha.2018.01.141] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 12/26/2017] [Accepted: 01/28/2018] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) chronic infection is a health problem in the worldwide, with a underlying higher risk of liver cirrhosis and hepaticocellular carcinoma. A number of studies indicate that microRNAs (miRNAs) play vital roles in HBV replication. This study was designed to explore the potential molecular mechanism of miR-200c in HBV replication. METHODS The expression of miR-200c, nuclear factor IA (NFIA) mRNA, HBV DNA, and HBV RNA (pregenomic RNA (pgRNA), and total RNA) were measured by qRCR. The levels of HBsAg and HBeAg were detected by ELISA. NFIA expression at protein level was measured by western blot. The direct interaction between miR-200c and NFIA were identified by Targetscan software and Dual-Luciferase reporter analysis. Enhance I activity were detected by Dual-Luciferase reporter assay. RESULTS miR-200c expression was prominently reduced in pHBV1.3-tranfected Huh7 and in stable HBV-producing cell line (HepG2.2.15). The enforced expression of miR-200c significantly suppressed HBV replication, as demonstrated by the reduced levels of HBV protein (HBsAg and HBeAg) and, DNA and RNA (pgRNA and total RNA) levels. NFIA was proved to be a target of miR-200c and NFIA overexpression notably stimulated HBV replication. In addition, the inhibitory effect of miR-200c on HBV Enhance I activity was abolished following restoration of NFIA. CONCLUSIONS miR-200c repressed HBV replication by directly targeting NFIA, which might provide a novel therapeutic target for HBV infection.
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Affiliation(s)
- Hui Tian
- Department of Infectious Disease, Huaihe Hospital of Henan University, Kaifeng 475000, China
| | - Zhenkun He
- Department of Infectious Disease, Huaihe Hospital of Henan University, Kaifeng 475000, China.
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Kim DH, Kang HS, Kim KH. Roles of hepatocyte nuclear factors in hepatitis B virus infection. World J Gastroenterol 2016; 22:7017-7029. [PMID: 27610013 PMCID: PMC4988315 DOI: 10.3748/wjg.v22.i31.7017] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 06/02/2016] [Accepted: 06/29/2016] [Indexed: 02/07/2023] Open
Abstract
Approximately 350 million people are estimated to be persistently infected with hepatitis B virus (HBV) worldwide. HBV maintains persistent infection by employing covalently closed circular DNA (cccDNA), a template for all HBV RNAs. Chronic hepatitis B (CHB) patients are currently treated with nucleos(t)ide analogs such as lamivudine, adefovir, entecavir, and tenofovir. However, these treatments rarely cure CHB because they are unable to inhibit cccDNA transcription and inhibit only a late stage in the HBV life cycle (the reverse transcription step in the nucleocapsid). Therefore, an understanding of the factors regulating cccDNA transcription is required to stop this process. Among numerous factors, hepatocyte nuclear factors (HNFs) play the most important roles in cccDNA transcription, especially in the generation of viral genomic RNA, a template for HBV replication. Therefore, proper control of HNF function could lead to the inhibition of HBV replication. In this review, we summarize and discuss the current understanding of the roles of HNFs in the HBV life cycle and the upstream factors that regulate HNFs. This knowledge will enable the identification of new therapeutic targets to cure CHB.
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Guo H, Liu H, Mitchelson K, Rao H, Luo M, Xie L, Sun Y, Zhang L, Lu Y, Liu R, Ren A, Liu S, Zhou S, Zhu J, Zhou Y, Huang A, Wei L, Guo Y, Cheng J. MicroRNAs-372/373 promote the expression of hepatitis B virus through the targeting of nuclear factor I/B. Hepatology 2011; 54:808-19. [PMID: 21608007 DOI: 10.1002/hep.24441] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2010] [Accepted: 05/10/2011] [Indexed: 12/12/2022]
Abstract
UNLABELLED MicroRNAs (miRNAs) play important roles in the posttranscriptional regulation of gene expression. Recent evidence has indicated the pathological relevance of miRNA dysregulation in hepatitis virus infection; however, the roles of microRNAs in the regulation of hepatitis B virus (HBV) expression are still largely unknown. In this study we identified that miR-373 was up-regulated in HBV-infected liver tissues and that the members of the miRs-371-372-373 (miRs-371-3) gene cluster were also significantly co-up-regulated in HBV-producing HepG2.2.15 cells. A positive in vivo association was identified between hepatic HBV DNA levels and the copy number variation of the miRs-371-3 gene cluster. The enhanced expression of miRs-372/373 stimulated the production of HBV proteins and HBV core-associated DNA in HepG2 cells transfected with 1.3×HBV. Further, nuclear factor I/B (NFIB) was identified to be a direct functional target of miRs-372/373 by in silico algorithms and this was subsequently confirmed by western blotting and luciferase reporter assays. Knockdown of NFIB by small interfering RNA (siRNA) promoted HBV expression, whereas rescue of NFIB attenuated the stimulation in the 1.3×HBV-transfected HepG2 cells. CONCLUSION Our study revealed that miRNA (miRs-372/373) can promote HBV expression through a pathway involving the transcription factor (NFIB). This novel model provides new insights into the molecular basis in HBV and host interaction.
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Affiliation(s)
- Hongyan Guo
- Medical Systems Biology Research Center, Department of Biomedical Engineering, Tsinghua University School of Medicine, Beijing, China
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Abstract
Hepatitis B virus (HBV) is tightly controlled by a number of noncytotoxic mechanisms. This control occurs within the host hepatocyte at different steps of the HBV replication cycle. HBV persists by establishing a nuclear minichromosome, HBV cccDNA, serving as a transcription template for the viral pregenome and viral mRNAs. Nucleoside/nucleotide analogues widely used for antiviral therapy as well as most antiviral cytokines act at steps after transcription of HBV RNAs and thus can control virus replication but do not directly affect its gene expression. Control of HBV at the level of transcription in contrast is able to restrict both, HBV replication and gene expression. In the review, we focus on how HBV is controlled at the level of transcription. We discuss how the composition of transcription factors determines HBV gene expression and replication and how this may be influenced by antivirally active substances, e.g. the cytokine IL-6 or helioxanthin analogues, or by the differentiation state of the hepatocyte.
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Affiliation(s)
- M Quasdorff
- Department of Gastroenterology and Hepatology, University Hospital Cologne, Germany
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7
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Abstract
Hepatitis B virus (HBV) is tightly controlled by a number of noncytotoxic mechanisms. This control occurs within the host hepatocyte at different steps of the HBV replication cycle. HBV persists by establishing a nuclear minichromosome, HBV cccDNA, serving as a transcription template for the viral pregenome and viral mRNAs. Nucleoside/nucleotide analogues widely used for antiviral therapy as well as most antiviral cytokines act at steps after transcription of HBV RNAs and thus can control virus replication but do not directly affect its gene expression. Control of HBV at the level of transcription in contrast is able to restrict both, HBV replication and gene expression. In the review, we focus on how HBV is controlled at the level of transcription. We discuss how the composition of transcription factors determines HBV gene expression and replication and how this may be influenced by antivirally active substances, e.g. the cytokine IL-6 or helioxanthin analogues, or by the differentiation state of the hepatocyte.
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Affiliation(s)
- M Quasdorff
- Department of Gastroenterology and Hepatology, University Hospital Cologne, Germany
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8
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Lee DH, Choi BH, Rho HM. The synergistic transactivation of the hepatitis B viral (HBV) pregenomic promoter by the E6 protein of human papillomavirus type 16 (HPV-16 E6) with HBV X protein was mediated through the AP1 site of E element in the enhancer I (EnI) in human liver cell. Biochem Biophys Res Commun 1999; 265:62-6. [PMID: 10548491 DOI: 10.1006/bbrc.1999.1636] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Infection by HBV of a cell already infected with other viral species or vice versa has been suggested as being involved in hepatocellular carcinoma. Using the CAT assay method, we investigated the interactive roles of HBx and potentially oncogenic and transactivating viral early proteins such as Ad5 E1A, HPV-16 E6, and SV40 T ag. In the presence of HBx, only HPV-16 E6 showed significant synergistic transactivation of EnI. We further investigated the function of the HPV-16 E6 using deletion, heterologous promoter, and mutation analyses on the EnI promoter. The results showed that the synergistic effect was mediated through the AP1 site of the E element in EnI by the direct activation of AP1 and support the idea that the infection by HBV of the cell with other viral species such as HPV-16 could increase the transcription activity of the HBV and other oncogenes containing an AP1 site in the promoter.
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Affiliation(s)
- D H Lee
- Department of Molecular Biology and Research Center for Cell Differentiation, Seoul National University, Seoul, 151-742, Korea
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9
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Park GT, Yi YW, Choi CY, Rho HM. A negative regulatory element and its binding protein in the upstream of enhancer II of hepatitis B virus. DNA Cell Biol 1997; 16:1459-65. [PMID: 9428794 DOI: 10.1089/dna.1997.16.1459] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The hepatitis B virus (HBV) core/pregenomic promoter is regulated by enhancer I (ENI) and enhancer II (ENII) which are located upstream of the initiation sites of core/pregenomic transcripts. In this study, we identified a negative regulatory element (NRE) (nt 1576 to 1639) upstream of ENII by serial deletion analysis; a 33 kDa cellular protein in HepG2 cells binds to this element. The NRE has a significant activity if it is located upstream of ENII in HepG2 cells. Mutational analysis showed that the sequence (5'-CCAC-3') from nt 1612 to 1615 is responsible for the repression activity of NRE. Southwestern blotting and UV-crosslinking assays with HepG2 nuclear extracts also demonstrated that the 33 kDa protein in HepG2 cells binds to the sequence. It, thus, appears that the 33 kDa protein is responsible for the repression activity of NRE.
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Affiliation(s)
- G T Park
- Department of Molecular Biology and Research Center for Cell Differentiation, Seoul National University, Korea
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10
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Abstract
Hepatitis B virus (HBV) e antigen (HBeAg) was discovered in 1972 as one of the serological markers of HBV infection. Although 25 years have passed since its initial discovery, the function of this antigen in the life cycle of HBV has remained elusive. Mutations in the HBV genome that prevent the expression of HBeAg do not abolish the replication of HBV, indicating that this antigen is not essential for HBV replication. In contrast, the conservation of the HBeAg gene in the genomes of related animal viruses, including the distantly related duck HBV, argues for an important function of this antigen. The purpose of the present article is to review the molecular biology of HBeAg and to examine its possible functions in the life cycle of HBV.
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Affiliation(s)
- J H Ou
- Department of Molecular Microbiology and Immunology, University of Southern California, School of Medicine, Los Angeles 90033, USA
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11
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Aragona E, Burk RD, Ott M, Shafritz DA, Gupta S. Cell type-specific mechanisms regulate hepatitis B virus transgene expression in liver and other organs. J Pathol 1996; 180:441-9. [PMID: 9014867 DOI: 10.1002/(sici)1096-9896(199612)180:4<441::aid-path713>3.0.co;2-c] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Intracellular expression of hepatitis B virus (HBV) was analysed in transgenic HBV mouse lines designated G7 and G26, the former lacking hepatitis B surface antigen (HBsAg) promoters. HBsAg mRNA expression was greater in the G26 line than in the G7 line, although in situ hybridization showed a qualitatively similar expression pattern in specific cell types. HBsAg mRNA was most abundant in hepatocytes, followed in magnitude by proximal renal tubular epithelial cells, pancreatic acinar cells, and epithelial cells of the gastric, small intestinal, and bronchiolar mucosae. In biliary epithelial cells, brain, spleen, large intestine, testis, heart, and skeletal muscle, HBsAg mRNA was undetectable. In cell transfection assays, the HBV enhancer/preS1 promoter efficiently expressed a luciferase reporter with appropriate upregulation by HNF-3 alpha and C/EBP alpha transcription factors in hepatocyte-derived cells but not in non-parenchymal epithelial liver cells or fibroblasts. These results suggest that cell-type specificity of HBV expression is regulated by interactions between viral elements and cellular transactivators. Variable expression of G7 and G26 HBV transgenes in epithelial cells combined with differences in transgene expression in similar sets of cells suggests at least two levels of regulation: one directing cell specificity of HBV expression and the other governing quantitative expression of HBV mRNA.
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Affiliation(s)
- E Aragona
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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12
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Gao B, Jiang L, Kunos G. Transcriptional regulation of alpha(1b) adrenergic receptors (alpha(1b)AR) by nuclear factor 1 (NF1): a decline in the concentration of NF1 correlates with the downregulation of alpha(1b)AR gene expression in regenerating liver. Mol Cell Biol 1996; 16:5997-6008. [PMID: 8887629 PMCID: PMC231602 DOI: 10.1128/mcb.16.11.5997] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
The 5' upstream region from --490 to --540 (footprint II) within the dominant P2 promoter of the rat alpha(1b) adrenergic receptor (alpha(1b)AR) gene is recognized by a sequence-specific DNA-binding protein (B. Gao, M. S. Spector, and G. Kunos, J. Biol. Chem. 270:5614-5619, 1995). This protein, detectable in Southwestern (DNA-protein) blots of crude nuclear extracts as 32- and 34-kDa bands, has been purified 6,000-fold from rat livers by DEAE-Sepharose, heparin-Sepharose, and DNA affinity chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and UV cross-linking of the purified protein indicated the same molecular mass as that in crude extracts. Methylation interference analysis revealed strong contact with a TTGGCT hexamer and weak contact with a TGGCGT hexamer in the 3' and 5' portions of footprint II, respectively. Nucleotide substitutions within these hexamers significantly reduced protein binding to footprint II and the promoter activity of P2 in Hep3B cells. The purified protein also bound to the nuclear factor 1 (NF1)/CTF consensus sequence, albeit with lower affinity. Gel mobility supershift and Western blotting (immunoblotting) analyses using an antibody against the NF1/CTF protein identified the purified 32- and 34-kDa polypeptides as NF1 or a related protein. Cotransfection into Hep3B cells or primary rat hepatocytes of cDNAs of the NF1-like proteins NF1/L, NF1/X, and NF1/Redl resulted in a three- to fivefold increase in transcription directed by wild-type P2 but not by the mutated P2. Partial hepatectomy markedly decreased the levels of NF1 in the remnant liver and its binding to P2, which paralleled declines in the rate of transcription of the alpha(1b)AR gene and in the steady-state levels of its mRNA. These observations indicate that NF1 activates transcription of the rat alpha(1b)AR gene via interacting with its P2 promoter and that a decline in the expression of NF1 is one of the mechanisms responsible for the reduced expression of the alpha(1b)AR gene during liver regeneration.
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Affiliation(s)
- B Gao
- Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
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Caselmann WH. Trans-activation of cellular genes by hepatitis B virus proteins: a possible mechanism of hepatocarcinogenesis. Adv Virus Res 1996; 47:253-302. [PMID: 8895834 DOI: 10.1016/s0065-3527(08)60737-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- W H Caselmann
- Department of Medicine II, Klinikum Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany
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Adams AD, Choate DM, Thompson MA. NF1-L is the DNA-binding component of the protein complex at the peripherin negative regulatory element. J Biol Chem 1995; 270:6975-83. [PMID: 7896848 DOI: 10.1074/jbc.270.12.6975] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The peripherin gene, which encodes a neuronal-specific intermediate filament protein, is transcriptionally induced with a late time course when nerve growth factor stimulates PC12 cells to differentiate into neurons. We have defined a negative regulatory element (NRE) that has a functional role in repressing peripherin expression in undifferentiate and nonneuronal cells. Nerve growth factor-induced derepression of peripherin gene expression is associated with alterations in proteins binding to a GC-rich DNA sequence in the NRE as detected by the DNA electrophoretic mobility shift assay (EMSA). We have utilized DNA affinity chromatography to purify from rat liver a 33-kDa DNA-binding protein that specifically recognizes the NRE. Microsequencing reveals identity with NF1-L, a member of the CTF/NF-1 transcription factor family. This protein forms a single complex when incubated with the NRE probe using EMSA analysis. The more slowly migrating complexes characteristic of crude undifferentiated PC12 cell extract are reconstituted by mixing the purified protein with the flow-through from the DNA affinity column, thereby demonstrating that protein-protein interactions are involved in complex formation. Supershift experiments incubating anti-CTF-1 antibody with undifferentiated PC12 cell extract prior to EMSA analysis confirm that NF1-L, or a closely related family member, is the DNA-binding protein component of the multiprotein complex at the NRE.
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Affiliation(s)
- A D Adams
- Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
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Chen CH, Chen PJ, Chu JS, Yeh KH, Lai MY, Chen DS. Fibrosing cholestatic hepatitis in a hepatitis B surface antigen carrier after renal transplantation. Gastroenterology 1994; 107:1514-8. [PMID: 7926515 DOI: 10.1016/0016-5085(94)90557-6] [Citation(s) in RCA: 73] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
A 45-year-old hepatitis B surface antigen carrier had an allograft kidney transplantation and maintenance immunosuppression with cyclosporin A and prednisolone. Six months later, she experienced a rapidly progressive hepatic failure manifested by elevation of serum bilirubin level, prolongation of prothrombin time, and mild to modest increase of serum aminotransferase levels. She died in 6 weeks. Postmortem liver histology showed canalicular and cellular cholestasis and ground-glass appearance and ballooning of most hepatocytes, but only mild inflammatory cell infiltration. Immunohistochemical staining showed massive loads of hepatitis B surface and core antigens in the hepatocytes and extensive periportal fibrosis. The whole picture was compatible with fibrosing cholestatic hepatitis described in hepatitis B virus-infected liver transplant. Sequencing of the hepatitis B virus genome amplified from the patient's serum indicated a precore mutant but few mutations in the core, pre-S, and S genes. Little inflammatory reaction was observed histologically despite HLA compatibility, a situation differing from that in liver transplant. This observation indicates that fibrosing cholestatic hepatitis may also occur in non-liver transplant setting.
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Affiliation(s)
- C H Chen
- Department of Internal Medicine, College of Medicine, National Taiwan University Hospital, Taipei
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Mason AL, Wick M, White HM, Benner KG, Lee RG, Regenstein F, Riely CA, Bain VG, Campbell C, Perrillo RP. Increased hepatocyte expression of hepatitis B virus transcription in patients with features of fibrosing cholestatic hepatitis. Gastroenterology 1993; 105:237-44. [PMID: 8514040 DOI: 10.1016/0016-5085(93)90032-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Recurrent hepatitis B after liver transplantation may be complicated by fibrosing cholestatic hepatitis. This syndrome is associated with rapid graft failure and is characterized by ballooning degeneration of hepatocytes and abundant viral antigen expression. METHODS To study this disorder further, in situ hybridization studies were performed on 36 liver biopsy specimens from 14 transplanted patients with recurrent hepatitis B and 18 nontransplanted controls with chronic hepatitis B. Biopsy specimens were scored for histological features and intensity of riboprobe hybridization signal to hepatitis B virus (HBV) DNA and RNA. RESULTS HBV DNA hybridization signals of 2+ to 3+ intensity were observed in 53% of the posttransplant biopsies but none of the nontransplanted samples (P < 0.001). HBV RNA signals of this intensity were found in 42% of the transplant biopsy specimens compared with 17% of the nontransplant specimens (P < 0.07). Features of fibrosing cholestatic hepatitis were noted in 12 biopsies; 11 of these displayed RNA signals of 2+ to 3+ intensity (92%) compared with 4 of 24 (17%) biopsy specimens without this diagnosis (P < 0.001). The level of hepatocyte RNA correlated with the extent of hepatocellular ballooning (P < 0.007). CONCLUSIONS These data suggest that fibrosing cholestatic hepatitis is associated with enhanced hepatitis B virus transcription and support a cytopathic role for the virus in the development of this syndrome.
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Affiliation(s)
- A L Mason
- Gastroenterology Section, St. Louis Veterans Affairs Medical Center, St. Louis, Missouri
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