The repressive activity of hepatitis C virus core protein on the transcription of p21waf1 is regulated by protein kinase A-mediated phosphorylation

Jung, Eun Young; Lee, Mi Nam; Yang, Hyo Young; Yu, Dae Yeul; Jang, Kyung Lib

doi:10.1016/s0168-1702(01)00335-5

Cited by 34 publications

(23 citation statements)

References 14 publications

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“…In contrast to the findings reported here, many previous reports suggest that both the structural and the NS proteins of HCV may have strong effects on host cell homeostasis and cell cycle control (3,11,19,21,23,27,30,37,39,43,56,(62)(63)(64). Most describe studies involving single gene expression experiments, often with highly active promoters resulting in significant protein overexpression to nonphysiologic levels and usually involving only a single viral protein, sometimes with a potentially critical domain deleted.…”

Section: Discussioncontrasting

confidence: 93%

“…In analyzing the cell cycle regulation in the clone 2-3 and clone 3 cells, we focused on the G 1 -S transition since previous reports suggest effects of HCV proteins on p53 and p21 function (2,11,13,19,27,29,30,39,43,50,51,60,62,63), which would be expected to predominantly affect the G 1 checkpoint. We did not specifically address whether an HCV-dependent alteration occurs at the G 2 /M border, since the absence of any gross changes in cell cycle distribution among asynchronously growing cells were not suggestive of this possibility (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…However, these reports contain many inconsistencies. Core, for example, has been described to both enhance and repress p21 function (11,21,23,27,29,37,43,50), actions that would be expected to exert opposing effects on cell cycle progression. The same is true for studies that have examined the impact of core protein on the regulation of apoptosis (12,23,49,56,65).…”

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confidence: 99%

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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

Scholle¹,

Li²,

Bodola³

et al. 2004

J Virol

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Hepatitis C is the most common cause of clinically significant liver disease in the United States. Although acute infection with hepatitis C virus (HCV) is usually subclinical, persistent infection develops in up to 80% of initially infected patients (2). The majority of persistently infected individuals develop evidence of chronic liver injury and are at risk for progressive hepatic fibrosis leading to cirrhosis and ultimately death due to liver failure or hepatocellular carcinoma. Approximately 10,000 individuals die each year with chronic liver disease associated with HCV infection in the United States alone (1), rendering this virus a very significant public health problem.HCV is classified within a distinct genus, Hepacivirus, in the family Flaviviridae (15). Its genome consists of positive sense, single-stranded RNA of approximately 9.5 kb in length (9). The genomic RNA contains a single open reading frame, from which one large polyprotein is expressed, and flanking 5Ј and 3Ј untranslated regions. Translation of the viral RNA occurs through a cap-independent mechanism via an internal ribosomal entry site (IRES) located in the 5Ј untranslated region. A combination of cellular and virally encoded protease activities leads to processing of the polyprotein into individual structural and nonstructural proteins. Three structural proteins have been identified with the core protein forming a poorly defined viral capsid, and E1 and E2, both glycosylated envelope proteins, forming heterodimers. These structural proteins are processed by host signal peptidases. C terminal to E2, further proteolytic processing by host peptidases yields a short hydrophobic peptide, p7, which may function as a membrane channel (44), followed by the nonstructural (NS) proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B. NS2 and the amino-terminal protease domain of NS3 are responsible for proteolytic cleavage at the NS2-NS3 junction (20, 52), whereas other proteolytic cleavage events involved in the maturation of the NS proteins are carried out by the major viral serine protease, NS3, in association with its cofactor, NS4A (5,7,35). In addition to its function as a protease, NS3 also contains helicase and nucleoside triphosphatase activities within its C-terminal domain (28). Specific replicative functions have not been identified for NS4B and NS5A, but both are likely to contribute to the viral replicase complex. NS5B constitutes the HCV RNA-dependent RNA polymerase and is thus the catalytic core of the replicase.In addition to functions related to RNA replication, both NS3/4A and NS5A appear to play important roles in modulating antiviral responses within infected cells and in promoting long-term persistence of the virus. The NS3/4A protease blocks

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Section: Discussioncontrasting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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

Scholle¹,

Li²,

Bodola³

et al. 2004

J Virol

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“…In addition, our previously published data and that by other groups have shown that a comparison of the phosphorylation intensities of the wild type and Serine mutants indicate that Ser99 and Ser116 of the core protein were the major phosphorylation sites for PKC and PKA, respectively. Modification of the core protein by phosphorylation may influence core functions (Shih et al, 1995;Jung et al, 2001;Lu et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Transgenic expression of Korean type hepatitis C virus core protein and related mutants in mice

et al. 2004

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“…Core protein demonstrated its tumorigenecity by inducing HCC in vivo in transgenic mice (Moriya et al, 1998). As a multifunctional regulator, core protein is known to deregulate cell cycle checkpoints by modulating transcription of the p21 gene (Jung et al, 2001). In addition, it can activate the expression of some proto-oncogenes (Ray et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Phospholipase D activity is elevated in hepatitis C virus core protein-transformed NIH3T3 mouse fibroblast cells

Kim

Choi²,

Jang³

et al. 2004

Exp Mol Med

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The repressive activity of hepatitis C virus core protein on the transcription of p21waf1 is regulated by protein kinase A-mediated phosphorylation

Cited by 34 publications

References 14 publications

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

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

Transgenic expression of Korean type hepatitis C virus core protein and related mutants in mice

Phospholipase D activity is elevated in hepatitis C virus core protein-transformed NIH3T3 mouse fibroblast cells

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