Title | Gamma 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. |
Publication Type | Journal Article |
Year of Publication | 2005 |
Authors | Zhang, HM, Yuan, J, Cheung, P, Chau, D, Wong, BW, McManus, BM, Yang, D |
Journal | Mol Cell Biol |
Volume | 25 |
Issue | 14 |
Pagination | 6247-58 |
Date Published | 2005 Jul |
ISSN | 0270-7306 |
Keywords | Animals, Apoptosis, Apoptosis Regulatory Proteins, bcl-2-Associated X Protein, Cell Cycle Proteins, Chemokine CXCL10, Chemokines, CXC, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, DNA-Binding Proteins, Enterovirus B, Human, Heart, HeLa Cells, Humans, Mice, Mitochondria, NF-kappa B, Oncogene Proteins, Viral, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, RNA Interference, RNA, Messenger, Transcriptional Activation, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Up-Regulation, Virus Replication |
Abstract | 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. |
DOI | 10.1128/MCB.25.14.6247-6258.2005 |
Alternate Journal | Mol. Cell. Biol. |
PubMed ID | 15988033 |
PubMed Central ID | PMC1168823 |