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Journal of Virology, February 2001, p. 1401-1407, Vol. 75, No. 3
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 (
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
/
) 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.
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