ABSTRACT
Transforming growth factor beta 1 (TGF-ß1) signal transduction has been implicated in many second-messenger pathways, including the NF-κB pathway. We provide evidence of a novel TGF-ß1-mediated pathway that leads to extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, which in turn induces expression of an Epstein-Barr virus (EBV) protein, ZEBRA, that is responsible for the induction of the viral lytic cycle. This pathway includes two unexpected steps, both of which are required to control ERK 1/2 phosphorylation: first, a quick and transient activation of NF-κB, and second, downregulation of inducible nitric oxide synthase (iNOS) activity that requires the participation of NF-κB activity. Although necessary, NF-κB alone is not sufficient to produce downregulation of iNOS, suggesting that another uncharacterized event(s) is involved in this pathway. Dissection of the steps involved in the switch from the EBV latent cycle to the lytic cycle will be important to understand how virus-host relationships modulate the innate immune system.
Subject(s)
Down-Regulation , Herpesvirus 4, Human/physiology , NF-kappa B/metabolism , Nitric Oxide Synthase Type II/metabolism , Transforming Growth Factor beta1/metabolism , Virus Activation , B-Lymphocytes/virology , Cell Line , Cell Line, Transformed , Gene Expression Regulation , Gene Expression Regulation, Viral , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/metabolism , Humans , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/genetics , Mitogen-Activated Protein Kinase 3/metabolism , NF-kappa B/genetics , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type II/genetics , Trans-Activators/genetics , Trans-Activators/metabolismABSTRACT
Epstein-Barr virus (EBV) a ubiquitous gamma herpesvirus persists for life, generally without health consequences. However, it is associated with several well-recognized malignancies, such as Burkitt's lymphoma and nasopharyngeal carcinoma. A growing list of malignancies has been proposed to be EBV-associated: most of which are consistently EBV-positive whereas others show inconsistent results. The possible contribution of EBV to the development and/or progression of different "non-classical" tumors is discussed in terms of putative "non-traditional'' infection in EBV-related tumors.
Subject(s)
Breast Neoplasms/virology , Liver Neoplasms/virology , Lymphatic Vessel Tumors/virology , Breast Neoplasms/complications , Carcinoma/complications , Carcinoma/virology , Disease Progression , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/virology , Female , Herpesvirus 4, Human/immunology , Humans , Liver Neoplasms/complications , Lymphatic Vessel Tumors/complications , Models, Biological , Salivary Gland Neoplasms/complications , Salivary Gland Neoplasms/virology , Stomach Neoplasms/complications , Stomach Neoplasms/virology , Uterine Cervical Neoplasms/complications , Uterine Cervical Neoplasms/virologyABSTRACT
Epstein-Barr virus, a ubiquitous human herpesvirus, is associated with the development of carcinomas and lymphomas. We previously showed that transforming growth factor beta1 (TGF-beta1) mediated the virus to enter the lytic cycle, which is triggered by expression of Z Epstein-Barr virus replication activator (ZEBRA), through the ERK 1/2 MAPK signaling pathway. We report here that Akt, activated downstream from ERK 1/2, was required for TGF-beta1-induced ZEBRA expression and enabled Smad3, a mediator of TGF-beta1 signaling, to be acetylated by direct interaction with the co-activator CREB-binding protein and then to regulate TGF-beta1-induced ZEBRA expression.
Subject(s)
CREB-Binding Protein/metabolism , Herpesvirus 4, Human/physiology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Smad3 Protein/metabolism , Transforming Growth Factor beta1/metabolism , Viral Proteins/metabolism , Virus Activation/physiology , Acetylation/drug effects , Cell Line, Tumor , Gene Expression Regulation, Viral/drug effects , Gene Expression Regulation, Viral/physiology , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Trans-Activators , Transforming Growth Factor beta1/pharmacology , Virus Activation/drug effectsABSTRACT
The Epstein-Barr virus (EBV) generally latently infects its target cells with expression of genes conferring resistance to apoptosis. However, the modulation of apoptotic signals during lytic cycle remains poorly understood. We show here that resulting from viral reactivation in the EBV-positive Mutu-I and Akata Burkitt's lymphoma cell lines, a two steps proteasome-dependent downregulation of expression of the proapoptotic protein BimEL occurs. The first drop might be EBV-independent, is ERK 1/2 dependent, and BimEL is phosphorylated on Ser69. A second dramatic drop of the BimEL level observed during the lytic cycle is dependent of EBV-late-gene expression, ERK 1/2 independent, and no further phosphorylation of BimEL on Ser69 occurred. These results demonstrate for the first time, that the lytic cycle contributes to downregulation of BimEL and then could add to protection against apoptosis.
