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(Received for publication, December 4, 1996, and in revised form, March 7, 1997)
From the Division of Infectious Diseases and Immunology, Saint
Louis University, St. Louis, Missouri 63110
ABSTRACT Our previous results have suggested that the
putative core protein of hepatitis C virus (HCV) transcriptionally
regulates cellular and viral genes, inhibits cisplatin and
c-myc-mediated apoptotic cell death under certain
conditions, and transforms primary rat embryo fibroblast cells with a
cooperative oncogene. Because HCV appears to cause hepatocellular
carcinoma, we evaluated the regulatory role of the HCV core protein on
p53, a well known tumor suppressor gene, by an in vitro
transfection assay. HCV core protein repressed transcriptional activity
of the p53 promoter when tested separately in COS7 and HeLa cells.
Deletion mutational analysis of the HCV core gene indicated that the
regulatory domain involved in the repression of p53 transcriptional
activity is located around amino acid residues 80-122 encompassing a
putative DNA binding motif and two major phosphorylation sites. Results from this study suggest that the putative core protein may have an
important biological role in the promotion of cell growth by repressing
p53 transcription, and this appears to be consistent with certain
earlier observations about HCV core moving into the nucleus.
INTRODUCTION Development of chronic hepatitis and the potential for disease
progression to hepatocellular carcinoma (1) are important features of
hepatitis C virus (HCV)1 infection in
humans. Successful purification of HCV from either infected tissues or
cultured cells has not been reported. It is possible that HCV is
stringently hepatotropic being restricted to replicate and release only
in differentiated hepatocytes, which may have HCV receptors on the cell
surface and specific functions that support viral growth (2). Thus it
is difficult to study the biological properties and pathogenicity of
the virus in the absence of unequivocal evidence for common ancestry of
HCV (3). The mechanism of HCV replication at the molecular level so far has depended upon comparative analysis and expression of its partial or
entire genome with those of distantly related flaviviruses or
pestiviruses (4). The virus genome encodes a single polyprotein precursor of ~3,000 amino acids (5) that is cleaved by both host and
viral proteases (6, 7) to generate three putative structural proteins
(core, E1, and E2) and at least six nonstructural proteins (NS2, NS3,
NS4A, NS4B, NS5A, and NS5B). The structural proteins are located in the
amino-terminal one-fourth of the polyprotein. The genomic region
encoding the putative core protein is relatively conserved (8). The
carboxyl terminus of the core protein has been established at amino
acid position 191. The HCV core protein demonstrates diverse biological
functions including the regulation of cellular and unrelated viral
genes at the transcriptional level (9), suppression of cisplatin and
c-myc-induced apoptosis (10), and transformation of REF
cells in cooperation with the H-ras oncogene (11).
Hepatocellular carcinoma accounts for over 90% of primary liver
cancers and may progress through the inactivation of the p53 gene via
mutations (12, 13). Because HCV appears to cause hepatocellular
carcinoma, in this study we evaluated the ability of the HCV core
protein to regulate the expression of p53 in a cotransfection system.
Our results suggested that the HCV core protein caused down-regulation
of p53, and this appeared to be consistent with the controversial
observations about HCV core moving into the nucleus.
EXPERIMENTAL PROCEDURES A partial cDNA clone (Blue4/C5p-1) of strain
HCV-1a containing the 5 COS7 and HeLa cells were
obtained from the American Type Culture Collection (Rockville, MD) and
grown in Dulbecco's modified Eagle's medium supplemented with 10%
fetal calf serum. Cells were transfected with the reporter (p53-CAT)
and an effector (HCV core) plasmid using lipofectamine (Life
Technologies, Inc.). Protein extracts were prepared 48 h after
transfection as described previously (9), and cell lysates were assayed
for CAT activity. To test the normalization of transfection efficiency,
duplicate sets of transfections were performed using pSV p53 mRNA synthesis, from the
transformed primary REF, was studied by RT-PCR as described previously
(16). Transformed REF cells were prepared by cotransfection with the
core gene construct and the cooperative H-ras oncogene as
described earlier (11). Briefly, cells were fed with fresh culture
medium 2-4 h before transfection. Cells were transfected with HCV core
gene (1 µg) alone or together with H-ras gene (1 µg) and
carrier salmon sperm DNA (18-19 µg) by calcium phosphate
coprecipitation (Bethesda Research Laboratories, Gaithersburg, MD). The
cells were washed with phosphate-buffered saline, fed with fresh medium
at 20 h post-transfection and refed every 4-6 days.
Morphologically transformed cells were separated after 3 weeks
following transfection. For negative control, a plasmid containing the
oncogene alone and the vector or antisense orientation of the HCV core
plasmid were used for comparison. Transformed cells were treated with
acid guanidinium thiocyanate-phenol-chloroform for extraction of the RNA. First strand cDNA was synthesized using random primer and avian myeloblastosis virus-reverse transcriptase. Sense
(5 RESULTS AND DISCUSSION A cotransfection assay was used to investigate the role of the HCV
core gene product on the transcription of the human p53 gene. COS7
cells were cotransfected with the plasmid encompassing the human p53
promoter linked to a reporter CAT gene (p53-CAT) and increasing amounts
of CMV Core1-191 plasmid DNA. The vector alone was also
used as a negative control in the cotransfection assay. A
representation of the CAT assay result is shown in Fig.
1A. Results from this experiment suggested that the core protein inhibits p53 promoter activity in a
dose-dependent manner. The CAT activity decreased
(20-85%) as the quantity of CMV Core1-191 plasmid DNA
was increased in the transfection of cells (Fig. 1A,
lanes 1-5). A similar effect was observed utilizing the
MuLV LTR-driven HCV core gene in a transfection with the human p53 promoter reporter construct in the transient transfection assay (Fig.
1B). An in vitro transient assay using a mouse
p53-CAT construct and the CMV Core1-191 plasmid DNAs was
also performed. HCV core protein displayed repressor activity on the
mouse p53 promoter (data not shown). Taken together, these results
suggested that repression of p53 promoter activity may be attributed to
the exogenous expression of the HCV core protein.
To determine whether HCV core protein-mediated p53 transcriptional
regulation is cell type-specific or may be influenced by the endogenous
expression of integrated E6 from human papilloma virus 18, we chose to
use human cervical carcinoma (HeLa) cells. A CAT assay was performed by
transfection of p53-CAT and different doses of the HCV core gene. The
mean results from at least three independent experiments are shown in
Table I. The results indicated that the inhibition of
p53 promoter activity by the HCV core protein was not limited to a
specific function in COS7 cells. The inhibition of p53 promoter
activity by the core protein might be due to a phenomenon called
squelching (18), where high levels of cotransfected activator proteins
have been shown to repress expression of certain genes through
sequestration of coactivators away from the promoter. To exclude the
possibility of squelching in the inhibition of p53 promoter activity by
HCV core protein, the core-mediated activation of the c-myc
promoter was tested. Under the same conditions, the core protein
stimulated the human c-myc promoter (>400% as the index)
and inhibited p53 promoter (68% as the index) activity in COS7 cells
(data not shown). Additionally, the dose-dependent regulation of p53 promoter activity (Fig. 1A) suggested that
the suppression is not due to squelching.
Effect of HCV core protein on p53 promoter
Volume 272, Number 17,
Issue of April 25, 1997
pp. 10983-10986
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
COMMUNICATION:
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
-untranslated region, C, E1, E2, and a portion
of the NS2 region kindly provided by Michael Houghton (Chiron
Corporation, Emeryville, CA) was used as a template for amplification
and cloning of the core genomic region (encompassing amino acids
1-191) into mammalian expression vectors following a similar procedure
described recently (11, 14). Briefly, two synthetic oligonucleotide primers, sense (5-GTGCTTGCGAATTCCCCGGGA-3) and antisense
(5-CGTGGAATTCGCACTTAGTAGG-3), containing EcoRI restriction
enzyme sites were used for PCR amplification. The amplified DNA was
inserted into the EcoRI site of the pcDNA3 mammalian
expression vector (Invitrogen, San Diego, CA) under the control of the
cytomegalovirus (CMV) early promoter (CMV Core1-191).
Alternatively, the PCR amplified genomic region was inserted into the
mammalian expression vector pBabe/puro bearing the Moloney murine
leukemia virus long terminal repeat (MuLV LTR). A 2.4-kilobase human
p53 promoter sequence (15) fused with the chloramphenicol acetyltransferase (p53-CAT), kindly provided by David Reisman (University of South Carolina), was used as a reporter plasmid to study
the role of the HCV core protein on the p53 promoter.
-gal and a
reporter plasmid, with or without the effector plasmid DNAs. One
transfection set was tested for expression of -galactosidase by cell
staining with
5-bromo-4-chloro-3-indolyl--D-galactopyranoside (9). A
comparable number (15-20% variation) of blue transfected cells expressing -galactosidase was observed. The other transfection set
was used for CAT assay. The acetylated and nonacetylated forms of
[14C]chloramphenicol were separated by thin layer
chromatography, autoradiographed, and scanned by a Molecular Dynamics
PhosphorImager. The level of CAT activity was calculated as the
percentage of the two acetylated forms of chloramphenicol relative to
the total amount of [14C]chloramphenicol. Duplicate
transfection experiments were repeated at least three times to verify
the reproducibility of the results.
-GAGGCGCTGCCCCCACCATGA-3, nucleotide positions 734-753) and
antisense (5-AGCTCTCGGAACATCTCGAAGC-3, nucleotide positions
1224-1245) synthetic oligonucleotide primers corresponding to the
nucleotide sequence of the p53 gene (17) were used in the RT-PCR for
the amplification of a specific genomic sequence. These selected
primers used in the RT-PCR amplification represent a conserved sequence
of both human and rat p53. A p53 cDNA, kindly provided by Arnold
Levine (Princeton University, NJ), was used as a positive control in
PCR amplification. A PCR amplified ~490-base pair fragment from the
p53 gene plasmid DNA was isolated by 1.2% agarose gel electrophoresis.
The DNA band from p53 plasmid was excised, eluted using an ultra-free
MC column (Millipore Corporation, Bedford, MA), and radiolabeled with
[
-32P]dCTP by random priming with a commercially
available kit (Boehringer Mannheim) for use as a probe. Reaction
products from different cycles of PCR were analyzed by 1.2% agarose
gel electrophoresis followed by Southern blot hybridization. The
autoradiogram was densitometrically scanned (Molecular Dynamics), and
the level of p53 expression in experimental and negative control cells
was compared.
Fig. 1.
Transcriptional repression of human p53
promoter activity by the HCV core protein under the control of CMV
early promoter (A) or MuLV-LTR promoter
(B). COS7 cells were transfected with 2 µg of the
p53-CAT reporter plasmid and HCV core expression plasmid in a
dose-dependent manner (A, lanes 1-5;
B, lanes 1 and 2). Cell extracts were
analyzed for CAT activity after 48 h of transfection.
[View Larger Version of this Image (65K GIF file)]
Amount of CMV Core (µg)
Cell type used
p53
status
CAT expressiona
Number of experiments
% of conversion
2
COS7
Wild
type
32.8 ± 2.1
5
4
COS7
Wild
type
3.0 ± 0.6
5
2
HeLa
Bound by
HPVE6b
37.2 ± 1.8
3
4
HeLa
Bound by
HPVE6
3.4 ± 0.9
3
a
Percentages of CAT activity presented as the
means ± S.D. indicate the extent of conversion with respect to
the basal level (100%) of p53 promoter-CAT gene construct.
To identify the domain responsible for suppression of p53 promoter
activity, a full-length clone and deletion mutants of the core gene
encompassing different lengths of amino acids (amino acids 1-55,
1-80, 1-122, and 80-191) were used in a CAT assay. The core gene
deletion mutants were tested for protein expression by an in
vitro transient expression. The CAT assay results of transcriptional regulation of the p53 promoter by the full-length and
HCV core gene deletion mutants and vector DNA are shown in Fig.
2. The results indicated that the core protein domain
required for the majority of p53 repression is located between amino
acid positions 80 and 122.
Fig. 2. Localization of the HCV core protein domain responsible for p53 promoter suppression. Schematic diagram of the deletion mutants of HCV core protein used is shown (A). COS7 cells were cotransfected with 2 µg of p53CAT reporter plasmid and 2 µg of the HCV core expression plasmid, and CAT assay was performed 48 h after transfection (B). Deletion mutant Core1-55 and the vector DNA negative control showed a similar level of activity on the p53 promoter. On the other hand, repression of p53 promoter activity was observed by the full-length Core1-191 or deletion mutants Core1-122 and Core1-80.
[View Larger Version of this Image (13K GIF file)]
To determine whether the endogenous p53 gene is repressed by the HCV core gene in HCVcore/H-ras transformed REF cells, the p53 mRNA level was measured by semiquantitative RT-PCR. The level of p53 mRNA present in the primary REF cells and HCV core transformed REF cells appeared to be similar. This observation is inconsistent with the CAT assay results presented here. However, it is possible that the level of the HCV core protein expression is different in HCV core/ras transformed REF cells than in an in vitro transient assay. HCV core protein-mediated repression of p53 may be an early event that precedes cellular transformation. Therefore p53 expression is no longer relevant in the transformed REF cells. Because p53 maintains the genetic integrity of cells by controlling progression through the cell cycle, the loss of p53 function appears therefore to be associated with increased genetic instability and the accumulation of mutations, which likely precede oncogenic transformation (19). Together, our observations suggest that the HCV core protein may exert a biological role for the promotion of cell growth by repression of p53 transcription during persistent infection. However, we did not observe a clear relationship between p53 and HCV core protein expression at this time, and the in vivo function of the core protein remains unclear.
Viral proteins may influence cellular genes, which in turn may be involved in the negative regulation of oncogenes or tumor suppressor genes. Inactivation of cellular genes may be a mechanism for the disruption of normal cell growth (20). Additionally, host factor has been identified as an important component for modulation of RNA virus replication (21). The HCV core protein is highly basic (isoelectric point 12.05) and could in principle show affinity toward nucleic acids and translocate to the nucleus during the mitotic phase, when the nuclear membrane is absent (22). Regions responsible for RNA and ribosome binding activities are probably located in the amino-terminal portion of the putative core protein (23). However, the presence of a putative DNA-binding motif, nuclear localization signals, phosphorylation sites, and the appearance of the core protein in the nucleus suggest its possible function as a gene regulatory protein (9, 24-27). Three different core protein products of ~21 (p21), 19 (p19), and 16 kDa (p16) have been reported (26). Both p21 and p19 displayed a cytoplasmic localization, whereas p16 shows localization to the nucleus. In regard to HCV genotype 1a, the production of the truncated p16 was associated with an amino acid substitution at codon 9 to a lysine residue. In contrast, the core protein of genotype 1b has been shown to lack nuclear localization (4, 26). Whether the difference in nuclear localization of the core protein is genotype-specific or cell type/cell cycle-specific or whether p16 is synthesized during virus replication in the infected cells remains to be examined. It is also not clear at this time if translocation of the putative core protein into the nucleus is affected by the expression of other HCV-associated proteins. HCV core protein exhibits promoter-specific differences in its mode of action. However, the mechanism by which the core protein regulates transcription remains to be elucidated.
Repression of the endogenous human p53 gene may have a biological implication in the development of hepatocellular carcinoma. The p53 gene encodes a tumor suppressor protein involved in maintaining the genetic integrity of the cell. Consistent with this, somatic mutations that are strongly implicated in the etiology of sporadic human malignancies, and germ line mutations in p53 are associated with a number of inherited cancers (19). A large number of patients with hepatocellular carcinoma are exposed to hepatitis B and/or hepatitis C virus, and a p53 mutation is found in a significant number of these patients (28). Reduced or inactivated p53 in HCV-infected cells would thus lead to the suppression of cell cycle arrest, leading to rapid progression through the requisite DNA damage repair cycle prior to genomic replication. Several DNA tumor viruses have been shown to interact with the p53 protein, functionally disabling p53 in the infected cells and possibly contributing to virus-dependent transformation (29-31). Recent studies suggest that retroviruses may differ from DNA tumor virus by influencing p53 transcription rather than directly interacting with p53 protein. Human immunodeficieny virus transactivator protein Tat transcriptionally represses p53 expression in T-cells, suggesting that Tat-mediated repression may contribute to human immunodeficieny virus-associated pathologies (32). Similarly, human T-cell leukemia virus type 1 Tax protein may promote malignant transformation through the repression of p53 transcription (33).
Cancer is a multi-step process that requires a cumulative effect altering both positive and negative regulators of cell proliferation and cell survival (34, 35). Inactivation of p53 is an important event in human cancer (19, 36). However, with the exception of functional inactivation of the p53 protein by viral proteins (33, 37), products of the MDM2 gene (38, 39) and PAX (40) and all previously reported examples of p53 inactivation in human tumors have been due to mutations within the p53 gene or gross chromosomal rearrangement within the p53 locus. Inhibition of p53 transcription by the core protein of HCV may serve as an important factor in this multi-step process. In addition, it is conceivable that the inappropriate expression of core protein (in the absence of viral morphogenesis) may contribute to malignancy by activating specific target genes, as well as by inactivating other inhibitory genes in addition to p53. Indeed, further study is necessary to correlate the expression level of p53 and core protein in HCV-mediated hepatocellular carcinoma.
FOOTNOTES
To whom correspondence should be addressed: Div. of Infectious
Disease and Immunology, Saint Louis University Health Sciences Center,
3635 Vista Ave., FDT-8N, St. Louis, MO 63110-0250. Tel.: 314-577-8648;
Fax: 314-771-3816.
1 The abbreviations used are: HCV, hepatitis C virus; CAT, chloramphenicol acetyltransferase; RT, reverse transcription; PCR, polymerase chain reaction; REF, rat embryo fibroblasts; CMV, cytomegalovirus; MuLV, Moloney murine leukemia virus; LTR, long terminal repeat.
ACKNOWLEDGEMENTS
We thank Robert B. Belshe for helpful discussions, Michael Houghton for providing the HCV cDNA (Blue4/C5p-1), Arnold Levine for p53 cDNA, David Reisman for the p53-CAT construct, and Kathy Banker for preparation of the manuscript.
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 M. Matto, C. M. Rice, B. Aroeti, and J. S. Glenn Hepatitis C Virus Core Protein Associates with Detergent-Resistant Membranes Distinct from Classical Plasma Membrane Rafts J. Virol., November 1, 2004; 78(21): 12047 - 12053. [Abstract] [Full Text] [PDF]
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A. Basu, R. Steele, R. Ray, and R. B. Ray Functional properties of a 16 kDa protein translated from an alternative open reading frame of the core-encoding genomic region of hepatitis C virus J. Gen. Virol., August 1, 2004; 85(8): 2299 - 2306. [Abstract] [Full Text] [PDF]
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 M. Nakaji, Y. Yano, T. Ninomiya, Y. Seo, K. Hamano, S. Yoon, M. Kasuga, T. Teramoto, Y. Hayashi, and H. Yokozaki IFN-alpha prevents the growth of pre-neoplastic lesions and inhibits the development of hepatocellular carcinoma in the rat Carcinogenesis, March 1, 2004; 25(3): 389 - 397. [Abstract] [Full Text] [PDF]
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F. Scholle, K. Li, F. Bodola, M. Ikeda, B. A. Luxon, and S. M. Lemon Virus-Host Cell Interactions during Hepatitis C Virus RNA Replication: Impact of Polyprotein Expression on the Cellular Transcriptome and Cell Cycle Association with Viral RNA Synthesis J. Virol., February 1, 2004; 78(3): 1513 - 1524. [Abstract] [Full Text] [PDF]
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 K. Watashi, M. Hijikata, A. Tagawa, T. Doi, H. Marusawa, and K. Shimotohno Modulation of Retinoid Signaling by a Cytoplasmic Viral Protein via Sequestration of Sp110b, a Potent Transcriptional Corepressor of Retinoic Acid Receptor, from the Nucleus Mol. Cell. Biol., November 1, 2003; 23(21): 7498 - 7509. [Abstract] [Full Text] [PDF]
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K. Herzer, C. S. Falk, J. Encke, S. T. Eichhorst, A. Ulsenheimer, B. Seliger, and P. H. Krammer Upregulation of Major Histocompatibility Complex Class I on Liver Cells by Hepatitis C Virus Core Protein via p53 and TAP1 Impairs Natural Killer Cell Cytotoxicity J. Virol., August 1, 2003; 77(15): 8299 - 8309. [Abstract] [Full Text] [PDF]
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D. Li, S. T. Takyar, W. B. Lott, and E. J. Gowans Amino acids 1-20 of the hepatitis C virus (HCV) core protein specifically inhibit HCV IRES-dependent translation in HepG2 cells, and inhibit both HCV IRES- and cap-dependent translation in HuH7 and CV-1 cells J. Gen. Virol., April 1, 2003; 84(4): 815 - 825. [Abstract] [Full Text] [PDF]
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 R. B. Birrer, D. Birrer, and J. V. Klavins Hepatocellular Carcinoma and Hepatitis Virus Ann. Clin. Lab. Sci., January 1, 2003; 33(1): 39 - 54. [Abstract] [Full Text] [PDF]
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 T. Isoyama, S. Kuge, and A. Nomoto The Core Protein of Hepatitis C Virus Is Imported into the Nucleus by Transport Receptor Kap123p but Inhibits Kap121p-dependent Nuclear Import of Yeast AP1-like Transcription Factor in Yeast Cells J. Biol. Chem., October 11, 2002; 277(42): 39634 - 39641. [Abstract] [Full Text] [PDF]
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 A H Mohsen, P Easterbrook, C B Taylor, and S Norris Hepatitis C and HIV-1 coinfection Gut, October 1, 2002; 51(4): 601 - 608. [Abstract] [Full Text] [PDF]
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M. N. Lee, E. Y. Jung, H. J. Kwun, H. K. Jun, D.-Y. Yu, Y. H. Choi, and K. L. Jang Hepatitis C virus core protein represses the p21 promoter through inhibition of a TGF-{beta} pathway J. Gen. Virol., September 1, 2002; 83(9): 2145 - 2151. [Abstract] [Full Text] [PDF]
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A. Bergqvist and C. M. Rice Transcriptional Activation of the Interleukin-2 Promoter by Hepatitis C Virus Core Protein J. Virol., January 15, 2001; 75(2): 772 - 781. [Abstract] [Full Text]
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T.-H. Wang, R. C. A. Rijnbrand, and S. M. Lemon Core Protein-Coding Sequence, but Not Core Protein, Modulates the Efficiency of Cap-Independent Translation Directed by the Internal Ribosome Entry Site of Hepatitis C Virus J. Virol., December 1, 2000; 74(23): 11347 - 11358. [Abstract] [Full Text]
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A. Naganuma, A. Nozaki, T. Tanaka, K. Sugiyama, H. Takagi, M. Mori, K. Shimotohno, and N. Kato Activation of the Interferon-Inducible 2'-5'-Oligoadenylate Synthetase Gene by Hepatitis C Virus Core Protein J. Virol., September 15, 2000; 74(18): 8744 - 8750. [Abstract] [Full Text]
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R. G. Hope and J. McLauchlan Sequence motifs required for lipid droplet association and protein stability are unique to the hepatitis C virus core protein J. Gen. Virol., August 1, 2000; 81(8): 1913 - 1925. [Abstract] [Full Text]
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H. Aoki, J. Hayashi, M. Moriyama, Y. Arakawa, and O. Hino Hepatitis C Virus Core Protein Interacts with 14-3-3 Protein and Activates the Kinase Raf-1 J. Virol., February 15, 2000; 74(4): 1736 - 1741. [Abstract] [Full Text]
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 A.-R. N. ZEKRI, A. A. BAHNASSY, S. M. SHAARAWY, O. A. MANSOUR, M. A. MADUAR, H. M. KHALED, and O. EL-AHMADI Hepatitis C virus genotyping in relation to neu-oncoprotein overexpression and the development of hepatocellular carcinoma J. Med. Microbiol., January 1, 2000; 49(1): 89 - 95. [Abstract] [Full Text] [PDF]
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 H. Huang, H. Fujii, A. Sankila, B. M. Mahler-Araujo, M. Matsuda, G. Cathomas, and H. Ohgaki {beta}-Catenin Mutations Are Frequent in Human Hepatocellular Carcinomas Associated with Hepatitis C Virus Infection Am. J. Pathol., December 1, 1999; 155(6): 1795 - 1801. [Abstract] [Full Text] [PDF]
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M. Gale Jr., B. Kwieciszewski, M. Dossett, H. Nakao, and M. G. Katze Antiapoptotic and Oncogenic Potentials of Hepatitis C Virus Are Linked to Interferon Resistance by Viral Repression of the PKR Protein Kinase J. Virol., August 1, 1999; 73(8): 6506 - 6516. [Abstract] [Full Text]
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N. Mamiya and H. J. Worman Hepatitis C Virus Core Protein Binds to a DEAD Box RNA Helicase J. Biol. Chem., May 28, 1999; 274(22): 15751 - 15756. [Abstract] [Full Text] [PDF]
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A. Ghosh, R Steele, K Meyer, R Ray, and R. Ray Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth J. Gen. Virol., May 1, 1999; 80(5): 1179 - 1183. [Abstract]
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L.-R. You, C.-M. Chen, T.-S. Yeh, T.-Y. Tsai, R.-T. Mai, C.-H. Lin, and Y.-H. W. Lee Hepatitis C Virus Core Protein Interacts with Cellular Putative RNA Helicase J. Virol., April 1, 1999; 73(4): 2841 - 2853. [Abstract] [Full Text]
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L.-R. You, C.-M. Chen, and Y.-H. W. Lee Hepatitis C Virus Core Protein Enhances NF-kappa B Signal Pathway Triggering by Lymphotoxin-beta Receptor Ligand and Tumor Necrosis Factor Alpha J. Virol., February 1, 1999; 73(2): 1672 - 1681. [Abstract] [Full Text]
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A. Shrivastava, S. K. Manna, R. Ray, and B. B. Aggarwal Ectopic Expression of Hepatitis C Virus Core Protein Differentially Regulates Nuclear Transcription Factors J. Virol., December 1, 1998; 72(12): 9722 - 9728. [Abstract] [Full Text] [PDF]
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T.-Y. Hsieh, M. Matsumoto, H.-C. Chou, R. Schneider, S. B. Hwang, A. S. Lee, and M. M. C. Lai Hepatitis C Virus Core Protein Interacts with Heterogeneous Nuclear Ribonucleoprotein K J. Biol. Chem., July 10, 1998; 273(28): 17651 - 17659. [Abstract] [Full Text] [PDF]
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K. Yasui, T. Wakita, K. Tsukiyama-Kohara, S.-I. Funahashi, M. Ichikawa, T. Kajita, D. Moradpour, J. R. Wands, and M. Kohara The Native Form and Maturation Process of Hepatitis C Virus Core Protein J. Virol., July 1, 1998; 72(7): 6048 - 6055. [Abstract] [Full Text] [PDF]
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J. Chang, S.-H. Yang, Y.-G. Cho, S. B. Hwang, Y. S. Hahn, and Y. C. Sung Hepatitis C Virus Core from Two Different Genotypes Has an Oncogenic Potential but Is Not Sufficient for Transforming Primary Rat Embryo Fibroblasts in Cooperation with the H-ras Oncogene J. Virol., April 1, 1998; 72(4): 3060 - 3065. [Abstract] [Full Text] [PDF]
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R. B. Ray, K. Meyer, R. Steele, A. Shrivastava, B. B. Aggarwal, and R. Ray Inhibition of Tumor Necrosis Factor (TNF-alpha )-mediated Apoptosis by Hepatitis C Virus Core Protein J. Biol. Chem., January 23, 1998; 273(4): 2256 - 2259. [Abstract] [Full Text] [PDF]
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M. Otsuka, N. Kato, K.-H. Lan, H. Yoshida, J. Kato, T. Goto, Y. Shiratori, and M. Omata Hepatitis C Virus Core Protein Enhances p53 Function through Augmentation of DNA Binding Affinity and Transcriptional Ability J. Biol. Chem., October 27, 2000; 275(44): 34122 - 34130. [Abstract] [Full Text] [PDF]
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