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Journal of Virology, February 2001, p. 1401-1407, Vol. 75, No. 3
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.3.1401-1407.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Hepatitis C Virus NS5A Physically Associates with p53 and Regulates p21/waf1 Gene Expression in a p53-Dependent Manner

Mainak Majumder,1 Asish K. Ghosh,1 Robert Steele,1 Ranjit Ray,2,3 and Ratna B. Ray1,2,*

Department of Pathology,1 Division of Infectious Diseases and Immunology,2 and Department of Molecular Microbiology and Immunology,3 Saint Louis University, St. Louis, Missouri 63104

Received 25 April 2000/Accepted 6 November 2000

We have previously demonstrated that hepatitis C virus (HCV) NS5A protein promotes cell growth and transcriptionally regulates the p21/waf1 promoter, a downstream effector gene of p53. In this study, we investigated the molecular mechanism of NS5A-mediated transcriptional repression of p21/waf1. We observed that transcriptional repression of the p21/waf1 gene by NS5A is p53 dependent by using p53 wild-type (+/+) and null (-/-) cells. Interestingly, p53-mediated transcriptional activation from a synthetic promoter containing multiple p53 binding sites (PG13-LUC) was abrogated following expression of HCV NS5A. Additional studies using pull-down experiments, in vivo coimmunoprecipitation, and mammalian two-hybrid assays demonstrated that NS5A physically associates with p53. Confocal microscopy revealed sequestration of p53 in the perinuclear membrane and colocalization with NS5A in transfected HepG2 and Saos-2 cells. Together these results suggest that an association of NS5A and p53 allows transcriptional modulation of the p21/waf1 gene and may contribute to HCV-mediated pathogenesis.

* Corresponding author. Mailing address: Department of Pathology, Saint Louis University, 1402 S. Grand Blvd., 4th Floor, St. Louis, MO 63104. Phone: (314) 577-8331. Fax: (314) 771-3816. E-mail: rayrb{at}slu.edu.

Journal of Virology, February 2001, p. 1401-1407, Vol. 75, No. 3
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.3.1401-1407.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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Copyright © 2001 by the American Society for Microbiology. All rights reserved.