Hepatitis c viral proteins interact with smad3 and differentially regulate tgf-β/smad3-mediated transcriptional activation

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. Access through your institution Buy or subscribe This is a preview of

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references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 Authors * Pei-Lin Cheng View author publications

You can also search for this author inPubMed Google Scholar * Meng-Hsiung Chang View author publications You can also search for this author inPubMed Google Scholar * Chi-Hong Chao View

author publications You can also search for this author inPubMed Google Scholar * Yan-Hwa Wu Lee View author publications You can also search for this author inPubMed Google Scholar

CORRESPONDING AUTHOR Correspondence to Yan-Hwa Wu Lee. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 26 April 2004 * Revised: 28 July 2004 * Accepted: 29 July 2004 * Published: 30 August 2004 * Issue Date: 14 October 2004

* DOI: https://doi.org/10.1038/sj.onc.1208066 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not

currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * HCV * core protein * NS3 protein * TGF-_β_ * Smad3 *

hepatocarcinogenesis