The in vivo binding site for oncoprotein c-Myc in the promoter for Epstein-Barr virus (EBV) encoding RNA (EBER) 1 suggests a specific role for EBV in lymphomagenesis.
BACKGROUND
Epstein-Barr virus (EBV) was isolated in the 1960s from the African childhood tumor, Burkitt's Lymphoma (BL), characterized by the translocation of the c-myc gene into one of the immunoglobulin loci. Due to the extreme discrepancy between the widespread dissemination of EBV infection and the overall rarity of EBV-related tumors, it remains an open question whether EBV is really a human tumor virus, and if so, what specific contribution EBV may have to tumorigenesis.


METHODS
Protein binding at the EBER locus of EBV was analyzed by genomic footprinting electrophoretic mobility shift, reporter gene assay, and chromatin immunoprecipitation in a panel of six B-cell lines.


RESULTS
Several novel in vivo protein binding sites were found in the EBER locus. Among those, a prominent binding site, 130 base pairs upstream of the EBER1 gene, contains two E-boxes providing a consensus sequence for binding of the transcription factor and oncoprotein c-Myc to the EBV genome.


CONCLUSIONS
Based on the discovery of a binding site for c-Myc in the EBV genome, a new molecular model for the specific role of EBV as a causal factor in the origin of endemic Burkitt's Lymphoma is proposed. Translocated and deregulated c-myc directly activates and maintains the antiapoptotic functions of the EBER locus in a single EBV-infected B cell undergoing the germinal center (GC) reaction. With the balance shifted towards cell survival, the oncogenic potential of the pro-apoptotic c-Myc protein is unmasked in the translocated GC cell. This single translocated and surviving cell is the founder cell of an endemic BL. The new model reinstitutes EBV as a real human tumor virus.
Niller
Hans H
HH
Institute for Medical Microbiology and Hygiene, University of Regensburg, Research Center, Regensburg, Germany. Hans-Helmut.Niller@klinik.uni-regensburg.de
Salamon
Daniel
D
Ilg
Karin
K
Koroknai
Anita
A
Banati
Ferenc
F
Bauml
Gerald
G
Rucker
Ovidiu
O
Schwarzmann
Fritz
F
Wolf
Hans
H
Minarovits
Janos
J
D001665:Binding Sites; D002461:Cell Line, Transformed; D002843:Chromatin / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D016259:Genes, myc / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006689:Hodgkin Disease / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008223:Lymphoma / Q000209:etiology* / Q000821:virology*; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics; D008957:Models, Genetic; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured
D002843:Chromatin; C099537:Epstein-Barr virus encoded RNA 1; D016271:Proto-Oncogene Proteins c-myc; D012367:RNA, Viral; D008156:Luciferases; D004121:Dimethyl Sulfoxide