Open AccessGamma Interferon-Inducible Protein 10 Induces HeLa Cell Apoptosis through a p53-Dependent Pathway Initiated by Suppression of Human Papillomavirus Type 18 E6 and E7 Expression
Author(s) -
Huifang M. Zhang,
Yuan Ji,
Paul Cheung,
David Chau,
Brian W. Wong,
Bruce M. McManus,
Decheng Yang
Publication year - 2005
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.25.14.6247-6258.2005
Subject(s) - biology , apoptosis , transfection , hela , signal transduction , interferon , microbiology and biotechnology , chemokine , viral replication , oncogene , cell culture , cell cycle , cancer research , virology , immunology , genetics , immune system
Gamma interferon-inducible protein 10 (IP10) is a member of the CXC family of chemokines. By differential mRNA display, we have demonstrated the upregulation of IP10 in coxsackievirus B3 (CVB3)-infected mouse hearts. Functional characterization of the IP10 gene in IP10-transfected Tet-On HeLa cells has found that IP10 induced cell apoptosis and inhibited viral replication. In the characterization of the IP10-induced apoptotic pathway, we found that overexpression of IP10 upregulated p53 and resulted in altered expression of p53-responsive genes such as the p21Cip1, p27kip1, NF-kappaB, Bax, and PUMA genes and the mitochondrial translocation of Bax. However, transduction of the IP10 cells with adenovirus expressing dominant negative p53 not only ablated p53-triggered gene expression but also abolished IP10-induced apoptosis and restored CVB3 replication to the control levels. These data suggest a novel mechanism by which IP10 inhibits viral replication through the induction of host cell death via a p53-mediated apoptotic pathway. We also found that constantly high-level expression of p53 in these tumor cells is attributed to the IP10-induced suppression of human papillomavirus E6 and E7 oncogene expression. Taken together, these data reveal not only a previously unrecognized link between chemokine IP10 and p53 in antiviral defense but also a mechanism by which IP10 inhibits tumor cell growth.