Transforming Growth Factor Beta 1 Stimulates Expression of the Epstein-Barr Virus BZLF1 Immediate-Early Gene Product ZEBRA by an Indirect Mechanism Which Requires the MAPK Kinase Pathway

Autor: Chantal Cochet, Paule Opolon, Irene Joab, Hassan Fahmi, Zakariae Hmama
Rok vydání: 2000
Předmět:
Gene Expression Regulation
Viral
MAPK/ERK pathway
Herpesvirus 4
Human
MAP Kinase Signaling System
Pyridines
viruses
Immunology
Smad2 Protein
SMAD
Microbiology
Immediate-Early Proteins
Smad7 Protein
Viral Proteins
Transforming Growth Factor beta
hemic and lymphatic diseases
Virology
Nitriles
Butadienes
Tumor Cells
Cultured
Humans
RNA
Messenger
Smad3 Protein
Enzyme Inhibitors
Promoter Regions
Genetic
Protein kinase A
Protein Kinase C
Protein kinase C
Smad4 Protein
Flavonoids
Regulation of gene expression
biology
Imidazoles
Transforming growth factor beta
Cyclic AMP-Dependent Protein Kinases
Molecular biology
Virus-Cell Interactions
BZLF1
DNA-Binding Proteins
Kinetics
Insect Science
Calcium-Calmodulin-Dependent Protein Kinases
Trans-Activators
biology.protein
Tetradecanoylphorbol Acetate
Immediate early gene
Zdroj: Journal of Virology. 74:5810-5818
ISSN: 1098-5514
0022-538X
Popis: Disruption of Epstein-Barr virus (EBV) latency is mediated by ZEBRA, the protein product of the immediate-early EBV gene, BZLF1. In vitro, phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC), induces reactivation of EBV. However, the physiological stimuli responsible for the disruption of viral latency are not well characterized. Transforming growth factor beta 1 (TGF-β1) has also been shown to trigger the reactivation of EBV in Burkitt lymphoma cell lines; however, the effect of TGF-β1 on ZEBRA expression has not been reported. To further understand this phenomenon, we have investigated the effect of TGF-β1 on ZEBRA expression. Our results indicate that the treatment of different EBV-positive Burkitt's lymphoma cell lines with TGF-β1 induces a time-dependent activation of BZLF1 transcription with a corresponding increase in the production of the protein ZEBRA. TGF-β1 has been shown to exert its effects through a wide range of intracellular routes; in the present study, we have explored these pathways. Transient expression of Smad proteins on their own had no effect on ZEBRA expression. A specific inhibitor of p38 mitogen-activated protein kinase (MAPK), SB203580, did not affect TGF-β1-induced ZEBRA expression, whereas treatment with the MAPK/ERK kinase inhibitors, PD98059 and U0126, dramatically decreased this induction. This suggests that TGF-β1 effect on BZLF1 expression requires the MAPK pathway. However, in Raji and B95-8 cells additional routes can be used, as (i) the inhibition of ZEBRA induction by PD98059 or U0126 was incomplete, whereas these inhibitors completely abolished PMA-induced ZEBRA expression, (ii) TGF-β1 induction of ZEBRA expression occurs in PKC-depleted cells, (iii) in Raji and in B95-8 cells, the effect of TGF-β1 and PMA are additive. Transient transfection of the EBV-negative B-cell line DG75 with a BZLF1 promoter-fusion construct (Zp-CAT) showed that under conditions where the BZLF1 promoter is activated by PMA treatment, TGF-β1 had no significant effect on the expression of the chloramphenicol acetyltransferase gene. Furthermore, TGF-β1 induction of BZLF1 transcripts is dependent on de novo protein synthesis, which suggests that TGF-β1 induces BZLF1 expression by an indirect mechanism.
Databáze: OpenAIRE
Externí odkaz: