Canonical NF-κB Activation Is Essential for Epstein-Barr Virus Latent Membrane Protein 1 TES2/CTAR2 Gene Regulation
| Autor: | Edward Bedoya, Elliott Kieff, John Quackenbush, Kaoru Takasaki, Jessica C. Mar, James Y. Zou, Megha Padi, Benjamin E. Gewurz, Bo Zhao, Ellen Cahir-McFarland, Nicholas P. Shinners |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Herpesvirus 4
Human Immunology Biology Microbiology Viral Matrix Proteins Virology otorhinolaryngologic diseases Humans Protein kinase A Gene Regulation of gene expression NF-kappa B Proteins RNA Epstein–Barr virus latent membrane protein 1 Molecular biology Up-Regulation Virus-Cell Interactions stomatognathic diseases RNA silencing IκBα HEK293 Cells Gene Expression Regulation Insect Science Signal transduction Signal Transduction |
| Zdroj: | Journal of Virology. 85:6764-6773 |
| ISSN: | 1098-5514 0022-538X |
| Popis: | Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) transforms rodent fibroblasts and is expressed in most EBV-associated malignancies. LMP1 ( t ransformation e ffector s ite 2 [TES2]/C-terminal activation region 2 [CTAR2]) activates NF-κB, p38, Jun N-terminal protein kinase (JNK), extracellular signal-regulated kinase (ERK), and interferon regulatory factor 7 (IRF7) pathways. We have investigated LMP1 TES2 genome-wide RNA effects at 4 time points after LMP1 TES2 expression in HEK-293 cells. By using a false discovery rate (FDR) of 2-fold changes in 1,916 mRNAs; 1,479 RNAs were upregulated and 437 were downregulated. In contrast to tumor necrosis factor alpha (TNF-α) stimulation, which transiently upregulates many target genes, LMP1 TES2 maintained most RNA effects through the time course, despite robust and sustained induction of negative feedback regulators, such as IκBα and A20. LMP1 TES2-regulated RNAs encode many NF-κB signaling proteins and secondary interacting proteins. Consequently, many LMP1 TES2-regulated RNAs encode proteins that form an extensive interactome. Gene set enrichment analyses found LMP1 TES2-upregulated genes to be significantly enriched for pathways in cancer, B- and T-cell receptor signaling, and Toll-like receptor signaling. Surprisingly, LMP1 TES2 and IκBα superrepressor coexpression decreased LMP1 TES2 RNA effects to only 5 RNAs, with FDRs of 2-fold changes. Thus, canonical NF-κB activation is critical for almost all LMP1 TES2 RNA effects in HEK-293 cells and a more significant therapeutic target than previously appreciated. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|