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

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Abstract

Transforming growth factor-β (TGF-β) is a pleiotropic cytokine implicated as a pathogenic mediator in various liver diseases. Enhanced TGF-β production and lack of TGF-β responses are often observed during hepatitis C virus (HCV) infection. In this study, we demonstrate that TGF-β-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-β/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 TGF-β, 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-β/Smad3-mediated apoptosis, only HCV core represses TGF-β-induced G1 phase arrest through downregulation of the TGF-β-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-β. In conclusion, HCV viral proteins interact with the TGF-β signaling mediator Smad3 and differentially impair TGF-β/Smad3-mediated transactivation and growth inhibition. This functional counteraction of TGF-β responses provides insights into possible mechanisms, whereby the HCV oncogenic proteins antagonize the host defenses during hepatocarcinogenesis.

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Acknowledgements

We thank CM Rice and Apath (St Louis, MO, USA) for generously providing the Ava.5 cells and p90/HCVFLlongpU plasmid. We also thank L-H Hwang, R-H Chen, C-K Chou, K-H Lan, K Tokushige and K Miyazono for providing plasmids used in this study. We are grateful to R Kirby for critical reading and comments on this manuscript. This work was supported by the following grants to Y-HW Lee: NSC 89-2315-B-010-006-MH, NSC 89-2320-B-010-121, NSC 90-2320-B-010-077, NSC 91-2320-B-010-040, and NSC 92-2320-B-010-064 from National Science Council; and in part by grants NHRI-EX91-9002BL, NHRI-EX92-9002BL, and NHRI-EX93-9002BL from the National Health Research Institute.

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  1. Institute of Biochemistry, National Yang-Ming University, Taipei, 112, Taiwan, Republic of China

    Pei-Lin Cheng, Meng-Hsiung Chang, Chi-Hong Chao & Yan-Hwa Wu Lee

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  1. Pei-Lin Cheng
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  2. Meng-Hsiung Chang
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Correspondence to Yan-Hwa Wu Lee.

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Cheng, PL., Chang, MH., Chao, CH. et al. Hepatitis C viral proteins interact with Smad3 and differentially regulate TGF-β/Smad3-mediated transcriptional activation. Oncogene 23, 7821–7838 (2004). https://doi.org/10.1038/sj.onc.1208066

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