105 results on '"Neuveut, Christine"'
Search Results
2. Molecular basis of the interaction of the human tyrosine phosphatase PTPN3 with the hepatitis B virus core protein
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Genera, Mariano, Quioc-Salomon, Barbara, Nourisson, Antonin, Colcombet-Cazenave, Baptiste, Haouz, Ahmed, Mechaly, Ariel, Matondo, Mariette, Duchateau, Magalie, König, Alexander, Windisch, Marc P., Neuveut, Christine, Wolff, Nicolas, and Caillet-Saguy, Célia
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- 2021
- Full Text
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3. A potential robust antiviral defense state in the common vampire bat: Expression, induction and molecular characterization of the three interferon-stimulated genes -OAS1, ADAR1 and PKR
- Author
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Sarkis, Sarkis, Dabo, Stéphanie, Lise, Marie-Claude, Neuveut, Christine, Meurs, Eliane F., Lacoste, Vincent, and Lavergne, Anne
- Published
- 2018
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4. Selective CXCR4 Antagonism by Tat: Implications for in vivo Expansion of Coreceptor Use by HIV-1
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Xiao, Hua, Neuveut, Christine, Tiffany, H. Lee, Benkirane, Monsef, Rich, Elizabeth A., Murphy, Philip M., and Jeang, Kuan-Teh
- Published
- 2000
5. HBx relieves chromatin-mediated transcriptional repression of hepatitis B viral cccDNA involving SETDB1 histone methyltransferase
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Rivière, Lise, Gerossier, Laetitia, Ducroux, Aurélie, Dion, Sarah, Deng, Qiang, Michel, Marie-Louise, Buendia, Marie-Annick, Hantz, Olivier, and Neuveut, Christine
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- 2015
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6. Hepatitis B Virus Pregenomic RNA in Hepatocellular Carcinoma: A Nosological and Prognostic Determinant
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Halgand, Boris, Desterke, Christophe, Rivière, Lise, Fallot, Guillaume, Sebagh, Mylène, Calderaro, Julien, Bioulac‐Sage, Paulette, Neuveut, Christine, Buendia, Marie‐Annick, Samuel, Didier, and Féray, Cyrille
- Published
- 2018
- Full Text
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7. Tridimensional infiltration of DNA viruses into the host genome shows preferential contact with active chromatin
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Moreau, Pierrick, Cournac, Axel, Palumbo, Gianna Aurora, Marbouty, Martial, Mortaza, Shogofa, Thierry, Agnes, Cairo, Stefano, Lavigne, Marc, Koszul, Romain, and Neuveut, Christine
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- 2018
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8. Targeting human telomerase reverse transcriptase with recombinant lentivector is highly effective to stimulate antitumor CD8 T-cell immunity in vivo
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Adotévi, Olivier, Mollier, Karine, Neuveut, Christine, Dosset, Magalie, Ravel, Patrice, Fridman, Wolf-Hervé, Tartour, Eric, Charneau, Pierre, Wain-Hobson, Simon, and Langlade-Demoyen, Pierre
- Published
- 2010
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9. Requirement for the second coding exon of Tat in the optimal replication of macrophage-tropic HIV-1
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Neuveut, Christine, Scoggins, Robert M., Camerini, David, Markham, Richard B., and Jeang, Kuan-Teh
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- 2003
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10. Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function
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Yedavalli, Venkat S.R.K., Neuveut, Christine, Ya-hui Chi, Kleiman, Lawrence, and Kuan-Teh Jeang
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HIV (Viruses) -- Research ,Chromosomes -- Research ,RNA -- Research ,Biological sciences - Abstract
The evidence that Rev/CRM1 (chromosome maintenance region 1) activity utilizes the ATO-dependent DEAD (D-E-A-D = Asp-Glu-Ala-Asp) box RNA helicase, DDX3 is presented. The DDX3 is a nucleo-cytoplasmic shuttling protein, which binds CRM1 and localizes to nuclear membrane pores.
- Published
- 2004
11. The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver
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Terradillos, Olivier, de La Coste, Alix, Pollicino, Teresa, Neuveut, Christine, Sitterlin, Delphine, Lecoeur, Hervé, Gougeon, Marie-Lise, Kahn, Axel, and Buendia, Marie-Annick
- Published
- 2002
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12. Compartmentalization of Hepatitis B variants in hepatocellular carcinoma: functional implication of HBx mutations: 45
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Halgand, Boris, Fallot, Guillaume, Riviere, Lise, Sebagh, Mylene, Buendia, Marie-Annick, Roque-Afonso, Anne-Marie, Gigou, Michelle, Neuveut, Christine, Samuel, Didier, and Feray, Cyrille
- Published
- 2012
13. Chapter 4 Hepatitis B Virus X Protein: Molecular Functions and Its Role in Virus Life Cycle and Pathogenesis
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Benhenda, Shirine, Cougot, Delphine, Buendia, Marie-Annick, and Neuveut, Christine
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- 2009
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14. HBV induced carcinogenesis
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Cougot, Delphine, Neuveut, Christine, and Buendia, Marie Annick
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- 2005
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15. Divergent subcellular locations of HTLV-I tax and Int-6: A contrast between in vitro protein-protein binding and intracellular protein colocalization
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Neuveut, Christine, Jin, Dong-Yan, Semmes, Oliver J., Diella, Francesca, Callahan, Robert, and Jeang, Kuan-Teh
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- 1997
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16. Impact of cellular autophagy on viruses: Insights from hepatitis B virus and human retroviruses
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Tang Sai-Wen, Ducroux Aurelie, Jeang Kuan-Teh, and Neuveut Christine
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Medicine - Abstract
Abstract Autophagy is a protein degradative process important for normal cellular metabolism. It is apparently used also by cells to eliminate invading pathogens. Interestingly, many pathogens have learned to subvert the cell’s autophagic process. Here, we review the interactions between viruses and cells in regards to cellular autophagy. Using findings from hepatitis B virus and human retroviruses, HIV-1 and HTLV-1, we discuss mechanisms used by viruses to usurp cellular autophagy in ways that benefit viral replication.
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- 2012
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17. Correction: The Tudor Domain Protein Spindlin1 Is Involved in Intrinsic Antiviral Defense against Incoming Hepatitis B Virus and Herpes Simplex Virus Type 1.
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Ducroux, Aurélie, Benhenda, Shirine, Rivière, Lise, Semmes, O. John, Benkirane, Monsef, and Neuveut, Christine
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HEPATITIS B virus ,PROTEIN domains ,HUMAN herpesvirus 1 ,HERPES simplex virus - Abstract
Graph: Fig 1 Spindlin1 interacts with HBx.(A) Coimmunoprecipitation of His-myc-Spindlin1 (His-myc-Spin1) with HA-HBx using anti-Myc antibodies in HEK293 cells. HEK293 cells were co-transfected with Flag-tagged HBx wt construct or the HBx alanine substitution mutants (F-HBx Cm5, F-HBx Cm7, F-HBx Cm8, F-HBx Cm9, F-HBx Cm13) and the His-myc-Spin1 plasmid. Cell extracts were immunoprecipitated with anti-Flag antibodies and analyzed by anti-Myc and anti-Flag immunoblot using the Odyssey system (right panel). [Extracted from the article]
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- 2020
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18. Virus de l'hépatite B et chromatine Une protéine virale, HBx, interfère avec la machinerie épigénétique de la cellule.
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Rivière, Lise, Gérossier, Laetitia, Hantz, Olivier, and Neuveut, Christine
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- 2016
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19. Human Liver Infection in a Dish: Easy-To-Build 3D Liver Models for Studying Microbial Infection.
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Petropolis, Debora B., Faust, Daniela M., Tolle, Matthieu, Rivière, Lise, Valentin, Tanguy, Neuveut, Christine, Hernandez-Cuevas, Nora, Dufour, Alexandre, Olivo-Marin, Jean-Christophe, and Guillen, Nancy
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LIVER disease diagnosis ,COMMUNICABLE disease diagnosis ,MORTALITY ,HOST-parasite relationships ,ENDOTHELIAL cells - Abstract
Human liver infection is a major cause of death worldwide, but fundamental studies on infectious diseases affecting humans have been hampered by the lack of robust experimental models that accurately reproduce pathogen-host interactions in an environment relevant for the human disease. In the case of liver infection, one consequence of this absence of relevant models is a lack of understanding of how pathogens cross the sinusoidal endothelial barrier and parenchyma. To fill that gap we elaborated human 3D liver in vitro models, composed of human liver sinusoidal endothelial cells (LSEC) and Huh-7 hepatoma cells as hepatocyte model, layered in a structure mimicking the hepatic sinusoid, which enable studies of key features of early steps of hepatic infection. Built with established cell lines and scaffold, these models provide a reproducible and easy-to-build cell culture approach of reduced complexity compared to animal models, while preserving higher physiological relevance compared to standard 2D systems. For proof-of-principle we challenged the models with two hepatotropic pathogens: the parasitic amoeba Entamoeba histolytica and hepatitis B virus (HBV). We constructed four distinct setups dedicated to investigating specific aspects of hepatic invasion: 1) pathogen 3D migration towards hepatocytes, 2) hepatocyte barrier crossing, 3) LSEC and subsequent hepatocyte crossing, and 4) quantification of human hepatic virus replication (HBV). Our methods comprise automated quantification of E. histolytica migration and hepatic cells layer crossing in the 3D liver models. Moreover, replication of HBV virus occurs in our virus infection 3D liver model, indicating that routine in vitro assays using HBV or others viruses can be performed in this easy-to-build but more physiological hepatic environment. These results illustrate that our new 3D liver infection models are simple but effective, enabling new investigations on infectious disease mechanisms. The better understanding of these mechanisms in a human-relevant environment could aid the discovery of drugs against pathogenic liver infection. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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20. The Tudor Domain Protein Spindlin1 Is Involved in Intrinsic Antiviral Defense against Incoming Hepatitis B Virus and Herpes Simplex Virus Type 1.
- Author
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Ducroux, Aurélie, Benhenda, Shirine, Rivière, Lise, Semmes, O. John, Benkirane, Monsef, and Neuveut, Christine
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HEPATITIS B virus ,LIVER cancer ,ANTIVIRAL agents ,EPIGENETICS ,PROTEINS in the body - Abstract
Hepatitis B virus infection (HBV) is a major risk factor for the development of hepatocellular carcinoma. HBV replicates from a covalently closed circular DNA (cccDNA) that remains as an episome within the nucleus of infected cells and serves as a template for the transcription of HBV RNAs. The regulatory protein HBx has been shown to be essential for cccDNA transcription in the context of infection. Here we identified Spindlin1, a cellular Tudor-domain protein, as an HBx interacting partner. We further demonstrated that Spindlin1 is recruited to the cccDNA and inhibits its transcription in the context of infection. Spindlin1 knockdown induced an increase in HBV transcription and in histone H4K4 trimethylation at the cccDNA, suggesting that Spindlin1 impacts on epigenetic regulation. Spindlin1-induced transcriptional inhibition was greater for the HBV virus deficient for the expression of HBx than for the HBV WT virus, suggesting that HBx counteracts Spindlin1 repression. Importantly, we showed that the repressive role of Spindlin1 is not limited to HBV transcription but also extends to other DNA virus that replicate within the nucleus such as Herpes Simplex Virus type 1 (HSV-1). Taken together our results identify Spindlin1 as a critical component of the intrinsic antiviral defense and shed new light on the function of HBx in HBV infection. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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21. Crosstalk between Hepatitis B Virus and the 3D Genome Structure.
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Dias, João Diogo, Sarica, Nazim, Cournac, Axel, Koszul, Romain, and Neuveut, Christine
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HEPATITIS B virus ,GENETIC regulation ,GENOMES ,DNA viruses ,GENETIC transcription regulation ,VIRAL genomes ,VIRAL hepatitis - Abstract
Viruses that transcribe their DNA within the nucleus have to adapt to the existing cellular mechanisms that govern transcriptional regulation. Recent technological breakthroughs have highlighted the highly hierarchical organization of the cellular genome and its role in the regulation of gene expression. This review provides an updated overview on the current knowledge on how the hepatitis B virus interacts with the cellular 3D genome and its consequences on viral and cellular gene expression. We also briefly discuss the strategies developed by other DNA viruses to co-opt and sometimes subvert cellular genome spatial organization. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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22. Diverse roles of hepatitis B virus in liver cancer.
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Fallot, Guillaume, Neuveut, Christine, and Buendia, Marie-Annick
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HEPATITIS B virus ,LIVER cancer ,DNA ,HOSTS (Biology) ,CHROMOSOMES ,APOPTOSIS ,IMMUNE response - Abstract
Hepatitis B virus (HBV) is a widespread human pathogen responsible for acute and chronic liver diseases. The hepatitis B burden is particularly heavy in endemic countries, where liver cirrhosis and hepatocellular carcinoma are leading causes of death. However, the oncogenic role of HBV remains enigmatic. As the virus has no cytopathic effect, liver damage is attributed to immune responses that induce inflammation, apoptosis and regeneration, fostering the accumulation of genetic and epigenetic alterations. In a more direct action, frequent integration of HBV DNA into host chromosomes may lead to insertional mutagenesis of cancer-related genes and chromosomal instability. HBV proteins, notably the HBx transactivator, participate as co-factors in oncogenesis. Better understanding of hepatitis B pathogenesis is mandatory for improving disease management. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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23. Inhibition of PP1 Phosphatase Activity by HBx: A Mechanism for the Activation of Hepatitis B Virus Transcription.
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Cougot, Delphine, Allemand, Eric, Rivière, Lise, Benhenda, Shirine, Duroure, Karine, Levillayer, Florence, Muchardt, Christian, Buendia, Marie-Annick, and Neuveut, Christine
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- 2012
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24. Mechanisms of HBV-related hepatocarcinogenesis
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Neuveut, Christine, Wei, Yu, and Buendia, Marie Annick
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HEPATITIS B virus , *CANCER risk factors , *LIVER cancer , *CARCINOGENESIS , *DNA viruses , *ONCOGENES , *CHRONIC active hepatitis , *ETIOLOGY of diseases , *ONCOGENIC viruses - Abstract
The hepatitis B virus (HBV) is a small enveloped DNA virus, which primarily infects hepatocytes and causes acute and persistent liver disease. Epidemiological studies have provided overwhelming evidence for a causal role of chronic HBV infection in the development of hepatocellular carcinoma, but the molecular mechanisms underlying virally-induced tumourigenesis remain largely debated. In the absence of a dominant oncogene encoded by the HBV genome, indirect roles have been proposed, including insertional activation of cellular cancer-related genes by HBV DNA integration, induction of genetic instability by viral integration or by the regulatory protein HBx, and long-term effects of viral proteins in enhancing immune-mediated liver disease. Recent genetic studies indicate that HBV-related tumours display a distinctive profile with a high rate of chromosomal alterations and low frequency of β-catenin mutations. This review will discuss the evidence implicating chronic HBV infection as a causal risk factor of primary liver cancer. It will also discuss the molecular mechanisms that are critical for the tumourigenic process due to long lasting infection with HBV. [Copyright &y& Elsevier]
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- 2010
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25. Liver Cell Transformation in Chronic HBV Infection.
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Benhenda, Shirine, Cougot, Delphine, Neuveut, Christine, and Buendia, Marie Annick
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LIVER cells ,CELL transformation ,HEPATITIS B virus ,LIVER cancer ,ONCOGENES ,CARCINOGENESIS ,CANCER genes ,VIRAL proteins - Abstract
Epidemiological studies have provided overwhelming evidence for a causal role of chronic HBV infection in the development of hepatocellular carcinoma (HCC), but the molecular mechanisms underlying virally-induced tumorigenesis remain largely debated. In the absence of a dominant oncogene encoded by the HBV genome, indirect roles have been proposed, including insertional activation of cellular oncogenes by HBV DNA integration, induction of genetic instability by viral integration or by the regulatory protein HBx, and long term effects of viral proteins in enhancing immune-mediated liver disease. In this chapter, we discuss different models of HBV-mediated liver cell transformation based on animal systems of hepadnavirus infection as well as functional studies in hepatocyte and hepatoma cell lines. These studies might help identifying the cellular effectors connecting HBV infection and liver cell transformation. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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26. Interaction and Functional Cooperation between the LIM Protein FHL2, CBP/p300, and β-Catenin.
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Labalette, Charlotte, Renard, Claire-Angélique, Neuveut, Christine, Annick#Buendia, Marie, and Yu Wei
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PROTEINS ,GENE expression ,ENZYMES ,GENETIC regulation ,MOLECULAR genetics ,ENZYME induction ,BIOCHEMICAL genetics - Abstract
Transcriptional activation of gene expression by Wnt signaling is driven by the association of β-catenin with TCF/LEF factors and the recruitment of transcriptional coactivators. It has been shown that the LIM protein FHL2 and the acetyltransferase CBP/p300 individually stimulate β-catenin transactivating activity and that β-catenin is acetylated by p300. Here, we report that FHL2 and CBP/p300 synergistically enhanced β-catenin/TCF-mediated transcription from Wnt-responsive promoters and that the acetyltransferase activity of CBP/ p300 was involved in the cooperation. CBP/p300 interacted directly with FHL2, predominantly through the CH3 domain but not the histone acetyltransferase domain, and different regions of CBP/p300 were involved in FHL2 and β-catenin binding. We provided evidence for the formation of a ternary complex by FHL2, CBP/p300, and β-catenin and for colocalization of the three proteins in the nucleus. In murine FHL2
-/- embryo fibroblasts, the transactivation activity of β-catenin/TCF was markedly reduced, and this defect could be restored by exogenous expression of FHL2. However, CBP/p300 were still able to coactivate the β-catenin/TCF complex in FHL2‘/-’ cells, suggesting that FHL2 is dispensable for the coactivator function of CBP/p300 on β-catenin. Furthermore, we found that FHL2 significantly increased acetylation of β-catenin by p300 in vivo. Finally, we showed that FHL2, CBP/p300, and β-catenin could synergistically activate androgen receptor-mediated transcription, indicating that the synergistic coactivator function is not restricted to TCF/LEF. [ABSTRACT FROM AUTHOR]- Published
- 2004
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27. Acetylation of β-Catenin by p300 Regulates β-Catenin-Tcf4 Interaction.
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Lévy, Laurence, Yu Wei, Labalette, Charlotte, Yuanfei Wu, Renard, Claire-Angélique, Buendia, Marie Annick, and Neuveut, Christine
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PHOSPHORYLATION ,EUKARYOTIC cells ,PROTEIN synthesis ,CELLS ,PAPILLOMAVIRUSES ,APOPTOSIS ,PROTEIN kinases ,GENES - Abstract
Lysine acetylation modulates the activities of nonhistone regulatory proteins and plays a critical role in the regulation of cellular gene transcription. In this study, we showed that the transcriptional coactivator p300 acetylated Β-catenin at lysine 345, located in arm repeat 6, in vitro and in vivo. Acetylation of this residue increased the affinity of 13-catenin for Tcf4, and the cellular Tcf4-bound pool of Β-catenin was significantly enriched in acetylated form. We demonstrated that the acetyltransferase activity of p300 was required for efficient activation of transcription mediated by Β-catenin/Tcf4 and that the cooperation between p300 and ~-catenin was severely reduced by the K345R mutation, implying that acetylation of ~3-catenin plays a part in the coactivation of Β-catenin by p300. Interestingly, acetylation of Β-catenin had opposite, negative effects on the binding of Β-catenin to the androgen receptor. Our data suggest that acetylation of Β-catenin in the arm 6 domain regulates Β-catenin transcriptional activity by differentially modulating its affinity for Tcf4 and the androgen receptor. Thus, our results describe a new mechanism by which p300 might regulate Β-catenin transcriptional activity. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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28. Selective CXCR4 antagonism by Tat: Implications for in vivo expansion of coreceptor use by HIV-1.
- Author
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Hua Xiao and Neuveut, Christine
- Subjects
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CHEMOKINES , *HIV infections , *TROPISMS - Abstract
Investigates the role of CXC chemokine receptor 4 (CXCR4) in HIV-1 infection and tropism. Role of Tat in binding and antagonization of CXCR4 function; Inhibition of tropic infection of cells; Detection of soluble Tat in HIV-1 seropositive individuals.
- Published
- 2000
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29. Early Steps of Hepatitis B Life Cycle: From Capsid Nuclear Import to cccDNA Formation.
- Author
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Diogo Dias, João, Sarica, Nazim, Neuveut, Christine, and Di Nunzio, Francesca
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HEPATITIS B ,CIRCULAR DNA ,PUBLIC health ,HEPATITIS B virus ,VIRAL replication - Abstract
Hepatitis B virus (HBV) remains a major public health concern, with more than 250 million chronically infected people who are at high risk of developing liver diseases, including cirrhosis and hepatocellular carcinoma. Although antiviral treatments efficiently control virus replication and improve liver function, they cannot cure HBV infection. Viral persistence is due to the maintenance of the viral circular episomal DNA, called covalently closed circular DNA (cccDNA), in the nuclei of infected cells. cccDNA not only resists antiviral therapies, but also escapes innate antiviral surveillance. This viral DNA intermediate plays a central role in HBV replication, as cccDNA is the template for the transcription of all viral RNAs, including pregenomic RNA (pgRNA), which in turn feeds the formation of cccDNA through a step of reverse transcription. The establishment and/or expression of cccDNA is thus a prime target for the eradication of HBV. In this review, we provide an update on the current knowledge on the initial steps of HBV infection, from the nuclear import of the nucleocapsid to the formation of the cccDNA. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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30. Oncogenic potential of TAR RNA binding protein TRBP and its regulatory interaction with RNA-dependent protein kinase PKR.
- Author
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Benkirane, Monsef, Neuveut, Christine, Chun, Rene F., Smith, Stephen M., Samuel, Charles E., Gatignol, Anne, and Kuan-Teh Jeang
- Subjects
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RNA , *CARRIER proteins , *PROTEIN kinases , *CELLULAR control mechanisms , *BIOLOGICAL transport , *CELL proliferation , *CARCINOGENESIS - Abstract
TAR RNA binding protein (TRBP) belongs to an RNA binding protein family that includes the double-stranded RNA-activated protein kinase (PKR), Drosophila Staufen and Xenopus xlrbpa. One member of this family, PKR, is a serine/threonine kinase which has anti-viral and anti-proliferative effects. In this study we show that TRBP is a cellular down-regulator of PKR function. Assaying expression from an infectious HIV-1 molecular clone, we found that PKR inhibited viral protein synthesis and that over-expression of TRBP effectively countered this inhibition. In intracellular and in cell-free assays we show that TRBP directly inhibits PKR autophosphorylation through an RNA binding-independent pathway. Biologically, TRBP serves a growth-promoting role; cells that over-express TRBP exhibit transformed phenotypes. Our results demonstrate the oncogenic potential of TRBP and are consistent with the notion that intracellular PKR function contributes physiologically towards regulating cellular proliferation. [ABSTRACT FROM AUTHOR]
- Published
- 1997
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31. Viral Load Affects the Immune Response to HBV in Mice With Humanized Immune System and Liver.
- Author
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Dusséaux, Mathilde, Masse-Ranson, Guillemette, Darche, Sylvie, Ahodantin, James, Li, Yan, Fiquet, Oriane, Beaumont, Elodie, Moreau, Pierrick, Rivière, Lise, Neuveut, Christine, Soussan, Patrick, Roingeard, Philippe, Kremsdorf, Dina, Di Santo, James P., and Strick-Marchand, Helene
- Abstract
Background & Aims Hepatitis B virus (HBV) infects hepatocytes, but the mechanisms of the immune response against the virus and how it affects disease progression are unclear. Methods We performed studies with BALB/c Rag2 –/– Il2rg –/– Sirpa NOD Alb-uPA tg/tg mice, stably engrafted with human hepatocytes (HUHEP) with or without a human immune system (HIS). HUHEP and HIS-HUHEP mice were given an intraperitoneal injection of HBV. Mononuclear cells were isolated from spleen and liver for analysis by flow cytometry. Liver was analyzed by immunohistochemistry and mRNA levels were measured by quantitative reverse transcription polymerase chain reaction (PCR). Plasma levels of HBV DNA were quantified by PCR reaction, and antigen-specific antibodies were detected by immunocytochemistry of HBV-transfected BHK-21 cells. Results Following HBV infection, a complete viral life cycle, with production of HBV DNA, hepatitis B e (HBe), core (HBc) and surface (HBs) antigens, and covalently closed circular DNA, was observed in HUHEP and HIS-HUHEP mice. HBV replicated unrestricted in HUHEP mice resulting in high viral titers without pathologic effects. In contrast, HBV-infected HIS-HUHEP mice developed chronic hepatitis with 10-fold lower titers and antigen-specific IgGs, (anti-HBs, anti-HBc), consistent with partial immune control. HBV-infected HIS-HUHEP livers contained infiltrating Kupffer cells, mature activated natural killer cells (CD69+), and PD-1+ effector memory T cells (CD45RO+). Reducing the viral inoculum resulted in more efficient immune control. Plasma from HBV-infected HIS-HUHEP mice had increased levels of inflammatory and immune-suppressive cytokines (C-X-C motif chemokine ligand 10 and interleukin 10), which correlated with populations of intrahepatic CD4+ T cells (CD45RO+PD-1+). Mice with high levels of viremia had HBV-infected liver progenitor cells. Giving the mice the nucleoside analogue entecavir reduced viral loads and decreased liver inflammation. Conclusion In HIS-HUHEP mice, HBV infection completes a full life cycle and recapitulates some of the immunopathology observed in patients with chronic infection. Inoculation with different viral loads led to different immune responses and levels of virus control. We found HBV to infect liver progenitor cells, which could be involved in hepatocellular carcinogenesis. This is an important new system to study anti-HBV immune responses and screen for combination therapies against hepatotropic viruses. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
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32. The Visna Transcriptional Activator TAT: Effects on the Viral LTR and on Cellular Genes
- Author
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Neuveut, Christine, Vigne, Robert, Clements, Janice E., and Sire, Josephine
- Published
- 1993
- Full Text
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33. Development of molecular and cellular tools to decipher the type I IFN pathway of the common vampire bat.
- Author
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Sarkis, Sarkis, Lise, Marie-Claude, Darcissac, Edith, Dabo, Stéphanie, Falk, Marcel, Chaulet, Laura, Neuveut, Christine, Meurs, Eliane F., Lavergne, Anne, and Lacoste, Vincent
- Subjects
- *
VAMPIRE bats , *RABIES virus , *IMMUNE system , *CELL lines , *PATTERN perception - Abstract
Though the common vampire bat, Desmodus rotundus , is known as the main rabies virus reservoir in Latin America, no tools are available to investigate its antiviral innate immune system. To characterize the IFN-I pathway, we established an immortalized cell line from a D. rotundus fetal lung named FLuDero. Then we molecularly characterized some of the Toll-like receptors (TLR3, 7, 8 and 9), the three RIG-I-like receptor members, as well as IFNα1 and IFNβ. Challenging the FLuDero cell line with poly (I:C) resulted in an up-regulation of both IFNα1 and IFNβ and the induction of expression of the different pattern recognition receptors characterized. These findings provide evidence of the intact dsRNA recognition machinery and the IFN-I signaling pathway in our cellular model. Herein, we generated a sum of insightful specific molecular and cellular tools that will serve as a useful model to study virus–host interactions of the common vampire bat. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
34. Single-Nucleotide Resolution Mapping of Hepatitis B Virus Promoters in Infected Human Livers and Hepatocellular Carcinoma.
- Author
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Altinel, Kübra, Hashimoto, Kosuke, Yu Wei, Neuveut, Christine, Gupta, Ishita, Suzuki, Ana Maria, Dos Santos, Alexandre, Moreau, Pierrick, Xia, Tian, Kojima, Soichi, Kato, Sachi, Takikawa, Yasuhiro, Hidaka, Isao, Shimizu, Masahito, Matsuura, Tomokazu, Tsubota, Akihito, Ikeda, Hitoshi, Nagoshi, Sumiko, Suzuki, Harukazu, and Michel, Marie-Louise
- Subjects
- *
HEPATITIS B virus , *LIVER cancer , *GENE expression , *NON-coding RNA , *GENETIC transcription , *LIVER failure - Abstract
Hepatitis B virus (HBV) is a major cause of liver diseases, including hepatocellular carcinoma (HCC), and more than 650,000 people die annually due to HBV-associated liver failure. Extensive studies of individual promoters have revealed that heterogeneousRNA5= ends contribute to the complexity ofHBVtranscriptome and proteome. Here, we provide a comprehensive map ofHBVtranscription start sites (TSSs) in human liver, HCC, and blood, as well as several experimental replication systems, at a single-nucleotide resolution. Using CAGE (cap analysis of gene expression) analysis of 16 HCC/nontumor liver pairs, we identify 17 robust TSSs, including a novel promoter for theXgene located in the middle of the gene body, which potentially produces a shorterXprotein translated from the conserved second start codon, and two minor antisense transcripts that might represent viral noncoding RNAs. Interestingly, transcription profiles were similar inHCCand nontumor livers, although quantitative analysis revealed highly variable patterns of TSS usage among clinical samples, reflecting precise regulation ofHBVtranscription initiation at each promoter. Unlike the variety of TSSs found in liver and HCC, the vast majority of transcripts detected in HBV-positive blood samples are pregenomic RNA, most likely generated and released from liver. Our quantitative TSS mapping using the CAGE technology will allow better understanding ofHBV transcriptional responses in further studies aimed at eradicatingHBVin chronic carriers. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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- View/download PDF
35. Methyltransferase PRMT1 Is a Binding Partner of HBx and a Negative Regulator of Hepatitis B Virus Transcription.
- Author
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Benhenda, Shirine, Ducroux, Aurélie, Rivière, Lise, Sobhian, Bijan, Ward, Michael D., Dion, Sarah, Hantz, Olivier, Protzer, Ulrike, Michel, Marie-Louise, Benkirane, Monsef, Semmes, Oliver J., Buendia, Marie-Annick, and Neuveut, Christine
- Subjects
- *
METHYLTRANSFERASES , *TRANSFERASES , *HEPATITIS B virus , *LIVER cancer , *TRANSCRIPTION factors - Abstract
The hepatitis B virus X protein (HBx) is essential for virus replication and has been implicated in the development of liver cancer. HBx is recruited to viral and cellular promoters and activates transcription by interacting with transcription factors and coactivators. Here, we purified HBx-associated factors in nuclear extracts from HepG2 hepatoma cells and identified protein arginine methyltransferase I (PRMT1) as a novel HBx-interacting protein. We showed that PRMT1 overexpression reduced the transcription of hepatitis B virus (HBV), and this inhibition was dependent on the methyltransferase function of PRMT1. Conversely, depletion of PRMT1 correlated with increased HBV transcription. Using a quantitative chromatin immunoprecipitation assay, we found that PRMT1 is recruited to HBV DNA, suggesting a direct effect of PRMT1 on the regulation of HBV transcription. Finally, we showed that HBx expression inhibited PRMT1-mediated protein methylation. Downregulation of PRMT 1 activity was further observed in HBV-replicating cells in an in vivo animal model. Altogether, our results support the notion that the binding of HBx to PRMT1 might benefit viral replication by relieving the inhibitory activity of PRMT1 on HBV transcription. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
36. The Four and a Half LIM-only Protein 2 (FHL2) Activates Transforming Growth Factor β(TGF-β) Signaling by Regulating Ubiquitination of the E3 Ligase Arkadia.
- Author
-
Tian Xia, Lévy, Laurence, Levillayer, Florence, Jia, Baosen, Gaiyun Li, Neuveut, Christine, Buendia, Marie-Annick, Ke Lan, and Yu Wei
- Subjects
- *
UBIQUITIN ligases , *UBIQUITINATION , *CELLULAR signal transduction , *TRANSFORMING growth factors-beta , *AUTOCATALYSIS , *PHYSIOLOGY - Abstract
Arkadia is a RING-based ubiquitin ligase that positively regulates TGF-β signaling by targeting several pathway components for ubiquitination and degradation. However, little is known about the mechanisms controlling Arkadia activity. Here we show that the LIM-only protein FHL2 binds and synergistically cooperates with Arkadia to activate Smad3/Smad4-dependent transcription. Knockdown of FHL2 by RNA interference decreases Arkadia level and restricts the amplitude of Arkadia-induced TGF-β target gene responses. We found that Arkadia is ubiquitinated via K63- and K27-linked polyubiquitination. A single mutation at the RING domain that abolishes the E3 activity diminishes Arkadia ubiquitination, indicating that this modification partly involves autocatalytic process. Mutation of seven lysines at the C-terminal region of Arkadia severely impairs ubiquitination through the K27 but not the K63 linkage and slows down the turnover of Arkadia, suggesting that K27-linked polyubiquitination might promote proteolysis-dependent regulation of Arkadia. We show that FHL2 increases the half-life of Arkadia through inhibition of ubiquitin chain assembly on the protein, which provides a molecular basis for functional cooperation between Arkadia and FHL2 in enhancing TGF-β signaling. Our study uncovers a novel regulatory mechanism of Arkadia by ubiquitination and identifies FHL2 as important regulator of Arkadia ubiquitination and TGF-β signal transduction. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
37. The Hepatitis B Virus X Protein Functionally Interacts with CREB-binding Protein/p300 in the Regulation of CREB-mediated Transcription.
- Author
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Cougot, Deiphine, Yuanfei Wu, Cairo, Stefano, Caramel, Julie, Renard, Claire-Angélique, Levy, Laurence, Buendia, Marie Annick, and Neuveut, Christine
- Subjects
- *
HEPATITIS B virus , *CARRIER proteins , *LIVER cancer , *VIRAL replication , *GENETIC transduction , *TRANSCRIPTION factors - Abstract
The hepatitis B virus infects more than 350 million people worldwide and is a leading cause of liver cancer. The virus encodes a multifunctional regulator, the hepatitis B virus X protein (HBx), that is essential for virus replication. HBx is involved in modulating signal transduction pathways and transcription mediated by various factors, notably CREB that requires the recruitment of the co-activators CREB-binding protein (CBP)/p300. Here we investigated the role of HBx and its potential interaction with CBP/p300 in regulating CREB transcriptional activity. We show that HBx and CBP/p300 synergistically enhanced CREB activity and that CREB phosphorylation by protein kinase A was a prerequisite for the cooperative action of HBx and CBP/p300. We further show that HBx interacted directly with CBP/p300 in vitro and in vivo. Using chromatin immunoprecipitation, we provide evidence that HBx physically occupied the CREB-binding domain of CREB-responsive promoters of endogenous cellular genes such as interleukin 8 and proliferating cell nuclear antigen. Moreover expression of HBx increased the recruitment of p300 to the interleukin 8 and proliferating cell nuclear antigen promoters in cells, and this is associated with increased gene expression. As recruitment of CBP/p300 is known to represent the limiting event for activating CREB target genes, HBx may disrupt this cellular regulation, thus predisposing cells to transformation. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
38. An in Vivo Replication-important Function in the Second Coding Exono f Tat Is Constrained against Mutation despite Cytotoxic T Lymphocyte Selection.
- Author
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Smith, Stephen M., Pentlicky, Sara, Klase, Zachary, Singh, Mahender, Neuveut, Christine, Chun-yi Lu, Christine, Reitz Jr., Marvin S., Yarchoan, Robert, Marx, Preston A., and Kuan-Teh Jeang
- Subjects
- *
EXONS (Genetics) , *PROTEINS , *GENETIC mutation , *LYMPHOCYTES - Abstract
Human and simian immunodeficiency virus (HIV/SIV) Tat proteins are specified by two coding exons. Tat functions in the transcription of primate lentiviruses. A plethora of in vitro data currently suggests that the second coding exon of Tat is largely devoid of function. However, whether the second exon of Tat contributes functionally to viral pathogenesis in vivo remains unknown. To address this question directly, we compared infection of rhesus macaques with an SIV, engineered to express only the first coding exon of Tat (SIVtat1ex), to counterpart infection with wild-type SIVmac239 virus, which expresses the full 2-exon Tat. This comparison showed that the second coding exon of Tat contributes to chronic SIV replication in vivo. Interestingly, in macaques, we observed a cytotoxic T lymphocytes (CTL) response to the second coding exon of Tat, which appears to durably control SIV replication. When SIV mutated in an attempt to escape this second Tat-exon-CTL, the resulting virus was less replicatively fit and failed to populate the host in vivo. Our study provides the first evidence that the second coding exon in Tat embodies an important function for in vivo replication. We suggest the second coding exon of Tat as an example of a functionally constrained "epitope" whose elicited CTL response cannot be escaped by virus mutation without producing a virus that replicates poorly in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
39. Identification of the LIM Protein FHL2 as a Coactivator of β-Catenin.
- Author
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Yu Wei, Renard, Claire-Angélique, Labalette, Charlotte, Yuanfei Wu, Lévy, Laurence, Neuveut, Christine, Prieur, Xavier, Flajolet, Marc, Prigent, Sylvie, and Buendia, Marie-Annick
- Subjects
- *
PROTEINS , *PROTEIN binding - Abstract
Studies the function of LIM-only protein 2 (FHL2) as coactivator of beta-catenin, a binding partner of E-cadherin in cell-cell adherens junctions. Role of beta-catenin; Interactional requirements; Effects of coexpression of beta-catenin and FHL2.
- Published
- 2003
- Full Text
- View/download PDF
40. Hepatitis B virus replicating in hepatocellular carcinoma encodes HBx variants with preserved ability to antagonize restriction by Smc5/6.
- Author
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Rivière, Lise, Quioc-Salomon, Barbara, Fallot, Guillaume, Halgand, Boris, Féray, Cyrille, Buendia, Marie-Annick, and Neuveut, Christine
- Subjects
- *
HEPATITIS B virus , *HEPATOCELLULAR carcinoma , *VIRUS diseases , *VIRAL proteins , *VIRAL replication , *TUMOR growth - Abstract
Hepatitis B virus infection is a major cause of liver diseases including hepatocellular carcinoma (HCC). The viral regulatory protein HBx is essential for viral replication and has been involved in the development of HCC. Recently, we characterized a subset of HCCs that replicate HBV. Our aim was to characterize HBx encoded by the full-length HBV DNA (cccDNA) in HCC and non-HCC liver. HBx genes were amplified and sequenced from eight paired HCC and non-HCC tissues in which HBV cccDNA and pgRNA were both present. Sequence analyses identified twelve amino acid positions mutated between HCC and non-HCC liver, and detected in at least three cases. We next assessed the impact of these mutations on HBx function by testing their transcriptional activity. We examined their ability to rescue the transcription of HBV virus deficient for HBx in differentiated HepaRG cells and to induce Smc5/6 degradation, which is mandatory for viral replication. We assessed their capacity to activate a CREB-dependent reporter. Finally we analyzed their growth suppressive activity using colony formation assays. Our results showed that most HBx variants isolated from HCC retain their ability to support HBV cccDNA transcription and to degrade Smc5/6. Strikingly, HCC specific HBx variants are impaired in their antiproliferative activity, which may be detrimental for tumor growth. In conclusion, in contrast to previous observations that tumor HBx variants lack transcriptional activity, we showed here that HBx variants have retained their ability to counteract Smc5/6 and thus to activate cccDNA transcription although they tend to lose antiproliferative activity. • HBV variants replicating in hepatocellular carcinoma are different from those replicating in the non tumoral liver. • Transcription of HBV cccDNA, which correlate with their ability to counteract the restriction factors Smc6/5. • Most HBx variants encoded by tumoral strains have lost their antiproliferative activity. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
41. Highlights from the 2023 International Meeting on the Molecular Biology of Hepatitis B virus.
- Author
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Allweiss L, Cohen C, Dias J, Fumagalli V, Guo H, Harris JM, Hu J, Iannacone M, Isogawa M, Jeng WJ, Kim KH, Kramvis A, Li W, Lucifora J, Muramatsu M, Neuveut C, Ploss A, Pollicino T, Protzer U, Tan A, Tanaka Y, Tu T, Tsukuda S, Thimme R, Urban S, Watashi K, Yuan Z, Yeh SH, McKeating JA, and Revill PA
- Subjects
- Humans, Molecular Biology, Japan, Hepatitis D virology, Host-Pathogen Interactions immunology, Host-Pathogen Interactions genetics, Hepatitis B virus genetics, Hepatitis B virus physiology, Hepatitis B virus immunology, Virus Replication, Hepatitis Delta Virus genetics, Hepatitis Delta Virus physiology, Hepatitis B virology, Hepatitis B immunology
- Abstract
Since its discovery in 1965, our understanding of the hepatitis B virus (HBV) replication cycle and host immune responses has increased markedly. In contrast, our knowledge of the molecular biology of hepatitis delta virus (HDV), which is associated with more severe liver disease, is less well understood. Despite the progress made, critical gaps remain in our knowledge of HBV and HDV replication and the mechanisms underlying viral persistence and evasion of host immunity. The International HBV Meeting is the leading annual scientific meeting for presenting the latest advances in HBV and HDV molecular virology, immunology, and epidemiology. In 2023, the annual scientific meeting was held in Kobe, Japan and this review summarises some of the advances presented at the Meeting and lists gaps in our knowledge that may facilitate the development of new therapies.
- Published
- 2024
- Full Text
- View/download PDF
42. Correction: The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription.
- Author
-
Cougot D, Wu Y, Cairo S, Caramel J, Renard CA, Lévy L, Buendia MA, and Neuveut C
- Published
- 2020
- Full Text
- View/download PDF
43. Hepatocellular carcinoma.
- Author
-
Buendia MA and Neuveut C
- Subjects
- Animals, Carcinogenesis, DNA, Viral, Disease Models, Animal, Hepatitis B Virus, Woodchuck genetics, Hepatitis B virus genetics, Humans, Marmota, Mice, Mice, Transgenic, Oncogenes, Trans-Activators genetics, Viral Regulatory and Accessory Proteins, Virus Integration, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular virology, Liver Cirrhosis virology, Liver Neoplasms genetics, Liver Neoplasms virology
- Abstract
The hepatitis B virus (HBV) is a widespread human pathogen that causes liver inflammation, cirrhosis, and hepatocellular carcinoma (HCC). Recent sequencing technologies have refined our knowledge of the genomic landscape and pathogenesis of HCC, but the mechanisms by which HBV exerts its oncogenic role remain controversial. In a prevailing view, inflammation, liver damage, and regeneration may foster the accumulation of genetic and epigenetic defects leading to cancer onset. However, a more direct and specific contribution of the virus is supported by clinical and biological observations. Among genetically heterogeneous HCCs, HBV-related tumors display high genomic instability, which may be attributed to the ability of HBV to integrate its DNA into the host cell genome, provoking chromosomal alterations and insertional mutagenesis of cancer genes. The viral transactivator HBx may also participate in transformation by deregulating diverse cellular machineries. A better understanding of the complex mechanisms linking HBV to HCC will improve prevention and treatment strategies., (Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
44. The four and a half LIM-only protein 2 (FHL2) activates transforming growth factor β (TGF-β) signaling by regulating ubiquitination of the E3 ligase Arkadia.
- Author
-
Xia T, Lévy L, Levillayer F, Jia B, Li G, Neuveut C, Buendia MA, Lan K, and Wei Y
- Subjects
- Animals, Binding Sites, Cell Line, Tumor, Fibroblasts cytology, Fibroblasts metabolism, Gene Expression Regulation, Genes, Reporter, Half-Life, Humans, LIM-Homeodomain Proteins metabolism, Luciferases, Mice, Muscle Proteins metabolism, Mutation, Nuclear Proteins metabolism, Protein Binding, Protein Structure, Tertiary, Signal Transduction, Transcription Factors metabolism, Transfection, Transforming Growth Factor beta metabolism, Ubiquitin metabolism, Ubiquitin-Protein Ligases metabolism, Ubiquitination, LIM-Homeodomain Proteins genetics, Muscle Proteins genetics, Nuclear Proteins genetics, Transcription Factors genetics, Transforming Growth Factor beta genetics, Ubiquitin genetics, Ubiquitin-Protein Ligases genetics
- Abstract
Arkadia is a RING-based ubiquitin ligase that positively regulates TGF-β signaling by targeting several pathway components for ubiquitination and degradation. However, little is known about the mechanisms controlling Arkadia activity. Here we show that the LIM-only protein FHL2 binds and synergistically cooperates with Arkadia to activate Smad3/Smad4-dependent transcription. Knockdown of FHL2 by RNA interference decreases Arkadia level and restricts the amplitude of Arkadia-induced TGF-β target gene responses. We found that Arkadia is ubiquitinated via K63- and K27-linked polyubiquitination. A single mutation at the RING domain that abolishes the E3 activity diminishes Arkadia ubiquitination, indicating that this modification partly involves autocatalytic process. Mutation of seven lysines at the C-terminal region of Arkadia severely impairs ubiquitination through the K27 but not the K63 linkage and slows down the turnover of Arkadia, suggesting that K27-linked polyubiquitination might promote proteolysis-dependent regulation of Arkadia. We show that FHL2 increases the half-life of Arkadia through inhibition of ubiquitin chain assembly on the protein, which provides a molecular basis for functional cooperation between Arkadia and FHL2 in enhancing TGF-β signaling. Our study uncovers a novel regulatory mechanism of Arkadia by ubiquitination and identifies FHL2 as important regulator of Arkadia ubiquitination and TGF-β signal transduction.
- Published
- 2013
- Full Text
- View/download PDF
45. Hepatitis B virus X protein molecular functions and its role in virus life cycle and pathogenesis.
- Author
-
Benhenda S, Cougot D, Buendia MA, and Neuveut C
- Subjects
- Animals, Apoptosis genetics, Carcinoma, Hepatocellular etiology, Carcinoma, Hepatocellular virology, DNA Repair genetics, Gene Expression Regulation, Viral, Hepatitis B virus genetics, Hepatitis B virus physiology, Humans, Liver Neoplasms etiology, Liver Neoplasms virology, Models, Biological, Trans-Activators genetics, Viral Regulatory and Accessory Proteins, Virus Replication genetics, Virus Replication physiology, Hepatitis B virus growth & development, Hepatitis B virus pathogenicity, Trans-Activators physiology
- Abstract
Despite the existence of effective vaccines, HBV infection remains a major health problem with 2 billion people infected worldwide. Among them, 350 million are chronically infected, a major risk factor for the development of hepatocellular carcinoma (HCC). There is a strong need to develop new and efficient treatments against chronic infection and HCC. It is therefore important to understand HBV replication and persistence as well as the role of HBV in liver carcinogenesis. This chapter focuses on the regulatory protein HBx which is thought to play a central role in HBV regulation and pathogenesis. HBx has been shown to modulate a myriad of viral and cellular functions, yet its role in virus replication and pathogenesis in infected individuals remains far from being completely understood.
- Published
- 2009
- Full Text
- View/download PDF
46. Tbx3 is a downstream target of the Wnt/beta-catenin pathway and a critical mediator of beta-catenin survival functions in liver cancer.
- Author
-
Renard CA, Labalette C, Armengol C, Cougot D, Wei Y, Cairo S, Pineau P, Neuveut C, de Reyniès A, Dejean A, Perret C, and Buendia MA
- Subjects
- Animals, Apoptosis physiology, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Cell Adhesion physiology, Cell Growth Processes physiology, Cell Line, Tumor, Genes, myc, Humans, Liver Neoplasms genetics, Liver Neoplasms pathology, Liver Neoplasms, Experimental genetics, Liver Neoplasms, Experimental metabolism, Liver Neoplasms, Experimental pathology, Mice, Mice, Transgenic, Mutation, Promoter Regions, Genetic, RNA, Small Interfering genetics, T-Box Domain Proteins genetics, TCF Transcription Factors genetics, TCF Transcription Factors metabolism, Transcription, Genetic, Transfection, beta Catenin biosynthesis, beta Catenin genetics, Liver Neoplasms metabolism, T-Box Domain Proteins biosynthesis, Wnt Proteins metabolism, beta Catenin metabolism
- Abstract
Tbx3 encodes a transcriptional repressor that is important for diverse patterning events during development, and Tbx3 mutation in humans causes the ulnar-mammary syndrome. Here, we describe the identification of Tbx3 in array-based search for genes downstream Wnt/beta-catenin that are implicated in liver tumorigenesis. Overexpression of Tbx3 is closely associated with the mutational status of beta-catenin in murine liver tumors induced by Myc as well as in human hepatocellular carcinomas and hepatoblastomas. Moreover, Tbx3 transcription is activated by ectopic expression of beta-catenin in mouse liver and in human tumor cell lines. Evidence that Tbx3 transcription is directly regulated by beta-catenin is provided by chromatin immunoprecipitation and reporter assays. Although HepG2 cells stably transfected with Tbx3 display moderately enhanced growth rate, the dominant negative mutant Tbx3-Y149S drastically inhibits hepatoma cell growth in vitro and in vivo. Moreover, small interfering RNAs (siRNA) directed against Tbx3 inhibit anchorage-independent growth of liver and colon carcinoma cells. We further show that inhibition of Tbx3 expression by specific siRNAs blocks beta-catenin-mediated cell survival and renders cells sensitive to doxorubicin-induced apoptosis. Conversely, ectopic expression of Tbx3 inhibits apoptosis induced by beta-catenin depletion. Marked overexpression of Tbx3 in a subset of hepatoblastomas is associated with chemotherapy-resistant phenotype and unfavorable patient outcome. These results reveal an unsuspected role of Tbx3 as a mediator of beta-catenin activities on cell proliferation and survival and as an important player in liver tumorigenesis.
- Published
- 2007
- Full Text
- View/download PDF
47. Immunogenic HLA-B*0702-restricted epitopes derived from human telomerase reverse transcriptase that elicit antitumor cytotoxic T-cell responses.
- Author
-
Adotévi O, Mollier K, Neuveut C, Cardinaud S, Boulanger E, Mignen B, Fridman WH, Zanetti M, Charneau P, Tartour E, Lemonnier F, and Langlade-Demoyen P
- Subjects
- Animals, Cancer Vaccines immunology, Cell Line, DNA, HLA-B Antigens genetics, HLA-B7 Antigen, Humans, Immunotherapy methods, Mice, Mice, Transgenic, Neoplasms immunology, Neoplasms therapy, Peptide Fragments, Plasmids, Vaccination, Vaccines, Synthetic immunology, DNA-Binding Proteins metabolism, Epitopes, T-Lymphocyte immunology, HLA-B Antigens immunology, Telomerase metabolism
- Abstract
Purpose: The human telomerase reverse transcriptase (hTERT) is considered as a potential target for cancer immunotherapy because it is preferentially expressed in tumor cells. To increase the applicability of hTERT-based immunotherapy, we set out to identify CTL epitopes in hTERT restricted by HLA-B*0702 molecule, a common MHC class I allele., Experimental Design: HLA-B*0702-restricted peptides from hTERT were selected by using a method of epitope prediction and tested for their immunogenicity in human (in vitro) and HLA-B*0702 transgenic mice (in vivo)., Results: All the six hTERT peptides that were predicted to bind to HLA-B*0702 molecule were found to induce primary human CTL responses in vitro. The peptide-specific CD8+ CTL lines were tested against various hTERT+ tumor cells. Although differences were observed according to the tumor origin, only three CTL lines specific for p277, p342, and p351 peptides exhibited cytotoxicity against tumor cells in a HLA-B*0702-restricted manner. In addition, this cytotoxicity was inhibited by the addition of peptide-loaded cold target cells and indicated that these epitopes are naturally processed and presented on the tumor cells. Further, in vivo studies using humanized HLA-B*0702 transgenic mice showed that all the candidate peptides were able to induce CTL responses after peptide immunization. Furthermore, vaccination with a plasmid DNA encoding full-length hTERT elicited peptide-specific CTL responses, indicating that these epitopes are efficiently processed in vivo., Conclusions: Together with previously reported hTERT epitopes, the identification of new CTL epitopes presented by HLA-B*0702 increases the applicability of hTERT-based immunotherapy to treating cancer.
- Published
- 2006
- Full Text
- View/download PDF
48. Interaction and functional cooperation between the LIM protein FHL2, CBP/p300, and beta-catenin.
- Author
-
Labalette C, Renard CA, Neuveut C, Buendia MA, and Wei Y
- Subjects
- Acetylation, Animals, Baculoviridae genetics, COS Cells, Cell Line, Cell Line, Tumor, Cell Nucleus metabolism, Cells, Cultured, Chlorocebus aethiops, Embryo, Mammalian cytology, Embryo, Nonmammalian, Fibroblasts metabolism, Glutathione Transferase metabolism, Homeodomain Proteins chemistry, Humans, Immunoblotting, LIM-Homeodomain Proteins, Luciferases metabolism, Muscle Proteins chemistry, Neoplasm Proteins chemistry, Precipitin Tests, Protein Structure, Tertiary, RNA analysis, Receptors, Androgen metabolism, Recombinant Proteins metabolism, Spodoptera cytology, Trans-Activators chemistry, Transcription Factors chemistry, Zinc Fingers, beta Catenin, Cadherins metabolism, Cytoskeletal Proteins metabolism, Homeodomain Proteins metabolism, Muscle Proteins metabolism, Neoplasm Proteins metabolism, Trans-Activators metabolism, Transcription Factors metabolism, Transcriptional Activation
- Abstract
Transcriptional activation of gene expression by Wnt signaling is driven by the association of beta-catenin with TCF/LEF factors and the recruitment of transcriptional coactivators. It has been shown that the LIM protein FHL2 and the acetyltransferase CBP/p300 individually stimulate beta-catenin transactivating activity and that beta-catenin is acetylated by p300. Here, we report that FHL2 and CBP/p300 synergistically enhanced beta-catenin/TCF-mediated transcription from Wnt-responsive promoters and that the acetyltransferase activity of CBP/p300 was involved in the cooperation. CBP/p300 interacted directly with FHL2, predominantly through the CH3 domain but not the histone acetyltransferase domain, and different regions of CBP/p300 were involved in FHL2 and beta-catenin binding. We provided evidence for the formation of a ternary complex by FHL2, CBP/p300, and beta-catenin and for colocalization of the three proteins in the nucleus. In murine FHL2(-/-) embryo fibroblasts, the transactivation activity of beta-catenin/TCF was markedly reduced, and this defect could be restored by exogenous expression of FHL2. However, CBP/p300 were still able to coactivate the beta-catenin/TCF complex in FHL2(-/-) cells, suggesting that FHL2 is dispensable for the coactivator function of CBP/p300 on beta-catenin. Furthermore, we found that FHL2 significantly increased acetylation of beta-catenin by p300 in vivo. Finally, we showed that FHL2, CBP/p300, and beta-catenin could synergistically activate androgen receptor-mediated transcription, indicating that the synergistic coactivator function is not restricted to TCF/LEF.
- Published
- 2004
- Full Text
- View/download PDF
49. Acetylation of beta-catenin by p300 regulates beta-catenin-Tcf4 interaction.
- Author
-
Lévy L, Wei Y, Labalette C, Wu Y, Renard CA, Buendia MA, and Neuveut C
- Subjects
- Acetylation, Amino Acid Sequence, Cell Line, Cytoskeletal Proteins chemistry, Cytoskeletal Proteins genetics, Genes, Reporter, Histone Acetyltransferases, Humans, Lysine metabolism, Molecular Sequence Data, Peptides metabolism, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, TCF Transcription Factors, Trans-Activators chemistry, Trans-Activators genetics, Transcription Factor 7-Like 2 Protein, Transcription, Genetic, Wnt Proteins, beta Catenin, p300-CBP Transcription Factors, Acetyltransferases metabolism, Cell Cycle Proteins metabolism, Cytoskeletal Proteins metabolism, DNA-Binding Proteins metabolism, Trans-Activators metabolism, Transcription Factors metabolism, Zebrafish Proteins
- Abstract
Lysine acetylation modulates the activities of nonhistone regulatory proteins and plays a critical role in the regulation of cellular gene transcription. In this study, we showed that the transcriptional coactivator p300 acetylated beta-catenin at lysine 345, located in arm repeat 6, in vitro and in vivo. Acetylation of this residue increased the affinity of beta-catenin for Tcf4, and the cellular Tcf4-bound pool of beta-catenin was significantly enriched in acetylated form. We demonstrated that the acetyltransferase activity of p300 was required for efficient activation of transcription mediated by beta-catenin/Tcf4 and that the cooperation between p300 and beta-catenin was severely reduced by the K345R mutation, implying that acetylation of beta-catenin plays a part in the coactivation of beta-catenin by p300. Interestingly, acetylation of beta-catenin had opposite, negative effects on the binding of beta-catenin to the androgen receptor. Our data suggest that acetylation of beta-catenin in the arm 6 domain regulates beta-catenin transcriptional activity by differentially modulating its affinity for Tcf4 and the androgen receptor. Thus, our results describe a new mechanism by which p300 might regulate beta-catenin transcriptional activity.
- Published
- 2004
- Full Text
- View/download PDF
50. Identification of the LIM protein FHL2 as a coactivator of beta-catenin.
- Author
-
Wei Y, Renard CA, Labalette C, Wu Y, Lévy L, Neuveut C, Prieur X, Flajolet M, Prigent S, and Buendia MA
- Subjects
- Cytoskeletal Proteins metabolism, Gene Expression Regulation, Neoplastic, HeLa Cells, Homeodomain Proteins metabolism, Humans, LIM-Homeodomain Proteins, Protein-Tyrosine Kinases metabolism, Proto-Oncogene Proteins metabolism, Trans-Activators metabolism, Wnt Proteins, beta Catenin, Cytoskeletal Proteins genetics, Homeodomain Proteins genetics, Muscle Proteins, Trans-Activators genetics, Transcription Factors, Transcriptional Activation, Zebrafish Proteins
- Abstract
Beta-catenin is a key mediator of the Wnt pathway, which plays a critical role in embryogenesis and oncogenesis. As a transcriptional activator, beta-catenin binds the transcription factors, T-cell factor and lymphoid enhancer factor, and regulates gene expression in response to Wnt signaling. Abnormal activation of beta-catenin has been linked to various types of cancer. In a yeast two-hybrid screen, we identified the four and a half of LIM-only protein 2 (FHL2) as a novel beta-catenin-interacting protein. Here we show specific interaction of FHL2 with beta-catenin, which requires the intact structure of FHL2 and armadillo repeats 1-9 of beta-catenin. FHL2 cooperated with beta-catenin to activate T-cell factor/lymphoid enhancer factor-dependent transcription from a synthetic reporter and the cyclin D1 and interleukin-8 promoters in kidney and colon cell lines. In contrast, coexpression of beta-catenin and FHL2 had no synergistic effect on androgen receptor-mediated transcription, whereas each of these two coactivators independently stimulated AR transcriptional activity. Thus, the ability of FHL2 to stimulate the trans-activating function of beta-catenin might be dependent on the promoter context. The detection of increased FHL2 expression in hepatoblastoma, a liver tumor harboring frequent beta-catenin mutations, suggests that FHL2 might enforce beta-catenin transactivation activity in cancer cells. These findings reveal a new function of the LIM coactivator FHL2 in transcriptional activation of Wnt-responsive genes.
- Published
- 2003
- Full Text
- View/download PDF
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