Physical and functional interaction between HCV core protein and the different p73 isoforms

Alisi, Anna; Giambartolomei, Stefania; Cupelli, Felicia; Merlo, Paola; Fontemaggi, Giulia; Spaziani, A.; Balsano, Clara

doi:10.1038/sj.onc.1206333

Cited by 63 publications

(49 citation statements)

References 43 publications

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“…Moreover, it has also been shown to induce hepatic adenomas in transgenic mice. These adenomas typically progress morphologically and biochemically to full malignant HCC (29). In this report, we evaluated the relationships between stable HCV core protein expression and its impact on the different cyclin-CDK complex activities involved in the control of cell growth.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…p73/core interaction results in the nuclear translocation of HCV core protein in the presence of the either p73a or p73b tumour suppressor proteins. The interaction with HCV core protein prevents p73a-, but not p73b-dependent cell growth arrest in a p53-dependent manner (Alisi et al, 2003). Hepatitis C virus core protein also modulates the expression of the cyclin-dependent kinase (CDK) inhibitor p21/Waf .…”

Section: Hepatitis C Virus Proteins and Host-cell Factorsmentioning

confidence: 99%

“…Hepatitis C virus core binds to the p53 (Ray et al, 1997;Lu et al, 1999), p73 (Alisi et al, 2003) and pRb (Cho et al, 2001) tumor suppressor proteins, but the functional consequences of these interactions have not fully been elucidated. p73/core interaction results in the nuclear translocation of HCV core protein in the presence of the either p73a or p73b tumour suppressor proteins.…”

Section: Hepatitis C Virus Proteins and Host-cell Factorsmentioning

confidence: 99%

Viral hepatitis and liver cancer: the case of hepatitis C

2006

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Chronic infection with the hepatitis C virus (HCV) is a major risk factor for the development of hepatocellular carcinoma (HCC) worldwide. The pathogenesis of HCC in HCV infection has extensively been analysed. Hepatitis C virus-induced chronic inflammation and the effects of cytokines in the development of fibrosis and liver cell proliferation are considered as one of the major pathogenic mechanisms. Increasing experimental evidence suggests that HCV contributes to HCC by directly modulating pathways that promote the malignant transformation of hepatocytes. Hepatitis C virus is an RNA virus that does not integrate into the host genome but HCV proteins interact with many host-cell factors well beyond their roles in the viral life cycle and are involved in a wide range of activities, including cell signaling, transcription, cell proliferation, apoptosis, membrane rearrangements, vesicular trafficking and translational regulation. At least four of the HCV gene products, namely HCV core, NS3, NS4B and NS5A, have been shown to exhibit transformation potential in tissue culture and several potentially oncogenic pathways have been shown to be altered by the expression of HCV proteins. Both HCV core and NS5A induce the accumulation of wild-type b-catenin and the Wnt-b-catenin pathway emerges as a common target for HCV (and HBV) in human HCCs, also independently from axin/b-catenin gene mutations. Induction of both endoplasmic reticulum stress and oxidative stress by HCV proteins might also contribute to HCV transformation. Most of the putative transforming functions of the HCV proteins have been defined in artificial cellular systems, which may not be applicable to HCV infection in vivo, and still need to be established in relevant infection and disease models.

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“…5). It has been shown that the p73 protein is regulated by diverse factors, including MDM2, MDMX, p300/ CBP, Amphiphysin IIb-1, ASPP (apoptosis-stimulated proteins of p53) 1 and 2, c-Abl (cellular Abelson oncogene), c-Myc, CTF2 (CCAATbinding transcription factor 2), Cyclin G, HCV (hepatitis C virus protein), MM1, PMS2 (mismatch-repair protein s2), WT1 (Wilms tumor protein), and YAP (Yes-associated protein) (15,16,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Among these regulators, MDM2 is a well known repressor of p73 and p53, but its inhibitory effect on p73 does not involve degradation.…”

Section: P19mentioning

confidence: 99%

p19 Interacts with and Activates p73 by Involving the MDM2 Protein

Jeong

Bae

Kim

et al. 2006

Journal of Biological Chemistry

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p73␤ is a structural and functional homologue of p53, a tumor suppressor gene. In this study, we identified a novel p73␤-binding protein, p19ras , by the yeast two-hybrid screening method. Alternative splicing of the proto-oncogene H-ras pre-mRNA has led to two distinct transcripts, p19 ras and p21 ras . In both endogenous and overexpressed systems, we confirmed that p19 ras binds to full-length p73␤ in vivo and in vitro. Coexpression of p19 ras with p73␤ stimulated the transcriptional activity of p73␤. Ras proteins are known to be small membrane-localized guanine nucleotide-binding proteins. However, unlike other Ras proteins, p19 ras is localized in the nucleus and the cytosol and its interaction with p73␤ occurred exclusively in the nucleus. Oncogenic MDM2 (mouse double minutes 2) is a known repressor of p73 transcriptional activity. In this study, when p19 ras was bound to MDM2, it further inhibited the association of MDM2 to the p73␤ protein. In addition, p19 ras abolished MDM2-mediated transcriptional repression of p73␤. Therefore, this study presents a novel pathway of Ras signaling that occurs in the nucleus, involving p19 ras and p73␤. Furthermore, a p19 rasmediated novel regulatory mechanism of p73 involving the MDM2 protein is described.More than a decade after the recognition of p53 as a major tumor suppressor, two p53 homologues, p73 and p63, were identified (1). The significant sequence homology between p73 and p53 suggests that the two proteins have similar functions as transcriptional factors. p73 not only activates the transcription of p53 target genes, but it also induces apoptosis and cell cycle arrest, like p53 (2, 3). However, a number of differences between p73 and p53 have been reported. p73 transactivates only certain p53-responsive genes (4, 5). Viral oncoproteins that bind to p53 and inhibit its activity do not interact with p73 (6, 7). Furthermore, the expression level of p73 is not affected by exposure to DNA-damaging agents that increase p53 levels, indicating that the two proteins have distinct cellular functions (8).MDM2 (mouse double minutes 2) is an oncoprotein that is overexpressed in many human cancers (9). It is well established that MDM2 inactivates p53 activity through monomeric ubiquitination of lysine residues of p53 (10 -12). In contrast, although p73 binds to MDM2 as well, their interaction does not lead to the proteosomal degradation of p73 (13). Nevertheless, the binding of p73 to MDM2 results in a dramatic inhibition of p73 transactivating activity (14). It has been shown that the binding to a cofactor, p300/CREB-binding protein (CBP), 3 is required for the transcriptional activity of p73 and that MDM2 competes with p73 for the p300/CBP (15). In a previous report, we demonstrated that Amphiphysin IIb-1 sequesters nascent p73 proteins in the cytoplasm and thus inhibits its transcriptional activity (16).Using the yeast two-hybrid screening method, we identified a novel p73␤-binding protein, p19ras , which is an alternative splicing variant of c-H-ras (17). Proto-oncogen...

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Physical and functional interaction between HCV core protein and the different p73 isoforms

Cited by 63 publications

References 43 publications

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

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

Viral hepatitis and liver cancer: the case of hepatitis C

p19 Interacts with and Activates p73 by Involving the MDM2 Protein

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