ABSTRACT
The tumor suppressor gene p53 plays a central role in the maintenance of normal cell growth and genetic integrity, while its impact on the Epstein-Barr virus (EBV) life cycle remains elusive. We found that p53 is important for histone deacetylase inhibitor-induced EBV lytic gene expression in nasopharyngeal carcinoma cells. Restoration of p53 in p53-null, EBV-infected H1299 cells augments the potential for viral lytic cycle initiation. Evidence from reporter assays demonstrated that p53 contributes to the expression of the immediate-early viral Zta gene. Further analysis indicated that the DNA-binding ability of p53 and phosphorylation of Ser392 may be critical. This study provides the first evidence that p53 is involved in the regulation of EBV lytic cycle initiation.
Subject(s)
Herpesvirus 4, Human/physiology , Histone Deacetylase Inhibitors , Trans-Activators/biosynthesis , Tumor Suppressor Protein p53/metabolism , Virus Activation , Cell Line, Tumor , Genetic Complementation Test , Humans , Tumor Suppressor Protein p53/deficiencyABSTRACT
Histone deactylase inhibitors (HDACi) are common chemotherapeutic agents that stimulate Epstein-Barr virus (EBV) reactivation; the detailed mechanism remains obscure. In this study, it is demonstrated that PKCdelta is required for induction of the EBV lytic cycle by HDACi. Inhibition of PKCdelta abrogates HDACi-mediated transcriptional activation of the Zta promoter and downstream lytic gene expression. Nuclear translocation of PKCdelta is observed following HDACi stimulation and its overexpression leads to progression of the EBV lytic cycle. Our study suggests that PKCdelta is a crucial mediator of EBV reactivation and provides a novel insight to study the regulation of the EBV lytic cycle.
Subject(s)
Enzyme Inhibitors/pharmacology , Epstein-Barr Virus Infections/virology , Herpesvirus 4, Human/physiology , Histone Deacetylase Inhibitors , Protein Kinase C-delta/physiology , Carbazoles/pharmacology , Cell Line, Tumor , Humans , Indoles/pharmacology , Maleimides/pharmacology , Nuclear Transfer Techniques , Promoter Regions, Genetic/genetics , Protein Kinase C/antagonists & inhibitors , Protein Kinase C/pharmacology , Trans-Activators/genetics , Transcriptional Activation , Viral Proteins/genetics , Virus Activation/drug effectsABSTRACT
BACKGROUND: Nasopharyngeal carcinoma (NPC) is associated with Epstein-Barr virus (EBV) and has high metastatic potential. Discoidin domain receptors (DDR1, DDR2) are receptor-type tyrosine kinases activated by collagen. Their ability to induce expression of matrix metalloproteinase is related with tumor invasion. Therefore, we aim to investigate DDRs gene expression and its regulation in NPC. METHODS AND RESULTS: By use of real-time quantitative polymerase chain reaction (Q-PCR), DDR2 gene expression but not DDR1 was significantly higher in primary and metastatic NPC. DDR2 was predominantly distributed in NPC tumor cells rather than in infiltrating lymphocytes. EBV Z-transactivator (Zta) transfection may distinctly elevate DDR2 level. Furthermore, data from reporter assay indicate that Zta could transactivate DDR2 promoter activity, suggesting the possible upregulation mechanism. CONCLUSION: DDR2 was differentially upregulated in NPC and modulated by EBV Zta protein. DDR2 may play a role in NPC invasion and serve as a diagnostic and therapeutic target.