Hepatitis C virus core protein promotes cell proliferation through the upregulation of cyclin E expression levels

Cho, Jae We; Baek, Won Ki; Suh, Seong Il; Yang, Se Hwan; Chang, Jun; Sung, Young Chul; Suh, Min Ho

doi:10.1034/j.1600-0676.2001.021002137.x

Cited by 50 publications

(39 citation statements)

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“…20 Thus, our findings are consistent with most studies suggesting a stimulatory effect of core protein on cell proliferation. However, the mechanisms proposed are diverse, ranging from cyclin E upregulation 9 and STAT3 phosphorylation 10 to activation of the mitogen-activated protein kinase pathway. 13 Using microarray analysis, we found differential transcription of genes associated with oncogenesis (14 genes), cell growth signaling or cell cycle regulation (9 genes), and apoptosis and negative control of cell growth (8 genes) (Tables 2, 3).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported to immortalize primary human hepatocytes 6 and to transform immortalized fibroblast cell lines either alone 7 or together with the H-Ras oncoprotein. 8 The core protein has also been found to stimulate growth of fibroblast cell lines, [8][9][10] but not a human osteosarcoma cell line. 11 There are conflicting reports as to whether the core protein stimulates the growth of human hepatoma cell lines.…”

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Hepatitis C virus core protein stimulates hepatocyte growth

et al. 2005

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Hepatitis C virus core protein stimulates hepatocyte growth

et al. 2005

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“…For instance, HCV core protein has been shown to target several cellular transcription factors such as hnRNP K (Hsieh et al, 1998), LZIP (Jin et al, 2000), 14-3-3 (Aoki et al, 2000), p21/WAF1 , and RNA helicase CAPRf (You et al, 1999), resulting in the alterations in the responsive transcription regulatory activities. Moreover, HCV core protein is able to cooperate with ras oncogene in the transformation of rodent fibroblasts under certain conditions (Chang et al, 1998), to influence host cell growth and proliferation through different mechanisms (Aoki et al, 2000;Cho et al, 2001;Erhardt et al, 2002), to promote immortalization of primary human hepatocytes (Ray et al, 2000), and to cause HCC formation at the late stage of transgenic mice (Moriya et al, 1998). Together, a growing body of evidence suggests the direct involvement of HCV core protein in the HCV-associated pathogenesis and carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Modulation of p53 transcription regulatory activity and post-translational modification by hepatitis C virus core protein

Kao

Chen

Chen³

et al. 2004

Oncogene

115

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Oncogenic virus proteins often target to tumor suppressor p53 during virus life cycle. In the case of hepatitis C virus (HCV) core protein, it has been shown to affect p53-dependent transcription. Here, we further characterized the in vitro and in vivo interactions between HCV core protein and p53 and showed that these two proteins colocalized in subnuclear granular structures and the perinuclear area. By use of a reporter assay, we observed that while low level of HCV core protein enhanced the transactivational activity of p53, high level of HCV core protein inhibited this activity. In both cases, however, HCV core protein increased the p53 DNA-binding affinity in gel retardation analyses, likely due to the hyperacetylation of p53 Lys 373 and Lys 382 residues. Additionally, HCV core protein, depending on its expression level, had differential effects on the Ser 15 phosphorylation of p53. Moreover, HCV core protein could rescue p53-mediated suppressive effects on both RNA polymerase I and III transcriptions. Collectively, our results indicate that HCV core protein targets to p53 pathway via at least three means: physical interaction, modulation of p53 gene regulatory activity and post-translational modification. This feature of HCV core protein, may potentially contribute to the HCV-associated pathogenesis.

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“…The analysis of HCV gene product(s), responsible for the impairment of cell cycle regulation, has already suggested a main role of HCV core protein in regulating hepatocyte proliferation, making cells susceptible to cellular transformation (8 -10). In fact, the ability of HCV core protein to accelerate the entry into S phase (8) and to up-regulate cyclin D1 and E expression has been reported in vitro (9).…”

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confidence: 99%

Role of p38 MAPK and RNA-dependent Protein Kinase (PKR) in Hepatitis C Virus Core-dependent Nuclear Delocalization of Cyclin B1

Spaziani

Alisi

Sanna

et al. 2006

Journal of Biological Chemistry

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Some hepatitis C virus (HCV) proteins, including core protein, deregulate the cell cycle of infected cells, thereby playing an important role in the viral pathogenesis of HCC. Thus far, there are only few studies that have deeply investigated in depth the effects of the HCV core protein expression on the progression through the G 1 /S and G 2 /M phases of the cell cycle. To shed light on the molecular mechanisms by which the HCV core protein modulates cell proliferation, we have examined its effects on cell cycle in hepatocarcinoma cells. We show here that HCV core protein perturbs progression through both the G 1 /S and the G 2 /M phases, by modulating the expression and the activity of several cell cycle regulatory proteins. In particular, our data provided evidence that core-dependent deregulation of the G 1 /S phase and its related cyclin-CDK complexes depends upon the ERK1/2 pathway. On the other hand, the viral protein also increases the activity of the cyclin B1-CDK1 complex via the p38 MAPK and JNK pathways. Moreover, we show that HCV core protein promotes nuclear import of cyclin B1, which is affected by the inhibition of both the p38 and the RNA-dependent protein kinase (PKR) activities. The important role of p38 MAPK in regulating G 2 /M phase transition has been previously documented. It is becoming clear that PKR has an important role in regulating both the G 1 /S and the G 2 /M phase, in which it induces M phase arrest. Based on our model, we now show, for the first time, that HCV core expression leads to deregulation of the mitotic checkpoint via a p38/PKR-dependent pathway. The hepatitis C virus (HCV)3 infection is a rapidly increasing public health problem, with millions of chronically infected patients to date. It is well known that patients with chronic disease have an increased risk of developing hepatocellular carcinoma (HCC) (1). Despite the research already done in this field, HCV-related mechanisms inducing cell transformation are still incompletely understood. Clinical observations indicate that the increased proliferation rate of hepatocytes is a major risk factor for the development of HCC (2). Several in vivo studies on hepatic biopsies reported an imbalance between the G 1 and the S phases of the cell cycle in liver cells obtained from chronic hepatitis C patients (3). Moreover, some studies revealed a G 2 /M dysfunction in hepatocarcinoma-derived cells (4). A large body of evidence has pointed to the possibility that HCV pathogenesis is due to virus-mediated disruption of several signal transduction pathways that normally regulate cell proliferation (5-7). However, the lack of appropriate cell culture systems and of suitable animal models that mimic viral propagation in humans has hampered the full understanding of HCV-dependent pathogenic mechanisms. The analysis of HCV gene product(s), responsible for the impairment of cell cycle regulation, has already suggested a main role of HCV core protein in regulating hepatocyte proliferation, making cells susceptible to cellular transforma...

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Hepatitis C virus core protein promotes cell proliferation through the upregulation of cyclin E expression levels

Abstract: Our data suggest that the HCV core protein promotes cell proliferation through upregulation of the cyclin E expression levels, implying this property of HCV core protein plays an important role in hepatocarcinogenesis.

Cited by 50 publications

References 26 publications

Hepatitis C virus core protein stimulates hepatocyte growth

Hepatitis C virus core protein stimulates hepatocyte growth

Modulation of p53 transcription regulatory activity and post-translational modification by hepatitis C virus core protein

Role of p38 MAPK and RNA-dependent Protein Kinase (PKR) in Hepatitis C Virus Core-dependent Nuclear Delocalization of Cyclin B1

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