Hepatitis C virus core protein represses the p21 promoter through inhibition of a TGF-β pathway

Lee, Mi Nam; Jung, Eun Young; Kwun, Hyun Jin; Jun, Hu; Yu, Dae Yeul; Choi, Yung Hyun; Jang, Kyung Lib

doi:10.1099/0022-1317-83-9-2145

Cited by 45 publications

(42 citation statements)

References 33 publications

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“…In this case, Smad3 activates p21 promoter by its ability to increase the binding of Sp1 protein to this specific Sp1 site (Zhang et al, 1998). In line with these, our results indicate that following TGF-b stimulation, the core protein, but not NS3, represses the binding of the Smad3/Sp1 complex to this specific Sp1 site (Figure 7f), which is consistent with the previous results showing that, with or without TGF-b treatment, the HCV core protein represses the p21 promoter via the Sp1 site (Ray et al, 1998;Dubordeau et al, 2002;Lee et al, 2002c). Thus, the core protein, but not NS3, may interfere with TGF-b-induced p21 promoter activity by disrupting Smad3/Sp1 complex formation or by blocking the DNA-binding affinity of this complex.…”

Section: Discussionsupporting

confidence: 93%

Hepatitis C viral proteins interact with Smad3 and differentially regulate TGF-β/Smad3-mediated transcriptional activation

et al. 2004

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Transforming growth factor-b (TGF-b) is a pleiotropic cytokine implicated as a pathogenic mediator in various liver diseases. Enhanced TGF-b production and lack of TGF-b responses are often observed during hepatitis C virus (HCV) infection. In this study, we demonstrate that TGF-b-mediated transactivation is decreased in cells exogenously expressing the intact HCV polyprotein. Among 10 viral products of HCV, only core and nonstructural protein 3 (NS3) physically interact with the MH1 (Mad homology 1) region of the Smad3 and block TGF-b/Smad3-mediated transcriptional activation through interference with the DNA-binding ability of Smad3, not the nuclear translocation. However, the interactive domain of NS3 extends to the MH2 (Mad homology 2) region of Smad3 and a distinction is found between effects mediated, respectively, by these two viral proteins. HCV core, in the presence or absence of TGFb, has a stronger suppressive effect on the DNA-binding and transactivation ability of Smad3 than NS3. Although HCV core, NS3, and the HCV subgenomic replicon all attenuate TGF-b/Smad3-mediated apoptosis, only HCV core represses TGF-b-induced G1 phase arrest through downregulation of the TGF-b-induced p21 promoter activation. Along with this, HCV core, rather than NS3, exhibits a significant inhibitory effect on the binding of Smad3/Sp1 complex to the proximal p21 promoter in response to TGF-b. In conclusion, HCV viral proteins interact with the TGF-b signaling mediator Smad3 and differentially impair TGF-b/Smad3-mediated transactivation and growth inhibition. This functional counteraction of TGF-b responses provides insights into possible mechanisms, whereby the HCV oncogenic proteins antagonize the host defenses during hepatocarcinogenesis.

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Section: Discussionsupporting

confidence: 93%

Hepatitis C viral proteins interact with Smad3 and differentially regulate TGF-β/Smad3-mediated transcriptional activation

et al. 2004

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“…In fact, many studies have demonstrated an interaction between viral oncogenic proteins and p21. For example, adenovirus E1A protein, 19 human papillomavirus E7 protein, 20 and hepatitis C virus core protein, 21 each bind to p21 and to the tumor suppressor protein, p53. p21 gene expression has also been shown to be regulated by viral proteins, including hepatitis C virus core protein 22 and HIV-1 Vpr protein.…”

Section: Introductionmentioning

confidence: 99%

The Role of Vpr in the Regulation of HIV-1 Gene Expression

Cui¹,

Tungaturthi²,

Ayyavoo³

et al. 2006

Cell Cycle

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“…Instead, viral proteins of HCV seem to be playing the major role in hepatocarcinogenesis. The proteins widely reported to be associated with HCV-mediated hepatocarcinogenesis are core, NS3 and NS5A proteins, which have all been shown to inhibit p21 WAF1 expression post-transcriptionally [41,42,43]. NS4A and NS4B each mediates translational inhibition, and probably increases degradation, of certain cellular proteins [44].…”

Section: Molecular Mechanisms Of Hepatocarcinogenesismentioning

confidence: 99%

From Molecular Biology to Targeted Therapies for Hepatocellular Carcinoma: The Future Is Now

Pang¹,

2007

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Hepatocellular carcinoma (HCC) is characterized as a highly chemoresistant cancer with no effective systemic therapy. Despite surgical or locoregional therapies, prognosis remains poor because of high tumor recurrence or tumor progression, and currently there are no well-established effective adjuvant therapies. The molecular biology of carcinogenesis and tumor progression of HCC has been increasingly understood with intense research in recent years. Several important intracellular signaling pathways such as the Ras/Raf/Mek/Erk pathway and PI3k/Akt/mTOR pathway have been recognized, and the role of several growth factors and angiogenic factors such as EGF and VEGF has been confirmed. Effective agents targeting these molecular abnormalities have been developed and widely tested in preclinical studies of HCC cell lines or xenograft models. Several agents have entered clinical trials in HCC patients, and recent data indicated that a multikinase inhibitor targeting Ras kinase and VEGFR-2, sorafenib, is effective in prolonging survival of patients with advanced HCC. The management of advanced HCC is entering the era of molecular targeting therapy, which is of particular significance for HCC in view of the lack of existing effective systemic therapy for this cancer.

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Hepatitis C virus core protein represses the p21 promoter through inhibition of a TGF-β pathway

Cited by 45 publications

References 33 publications

Hepatitis C viral proteins interact with Smad3 and differentially regulate TGF-β/Smad3-mediated transcriptional activation

Hepatitis C viral proteins interact with Smad3 and differentially regulate TGF-β/Smad3-mediated transcriptional activation

The Role of Vpr in the Regulation of HIV-1 Gene Expression

From Molecular Biology to Targeted Therapies for Hepatocellular Carcinoma: The Future Is Now

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