The latent membrane protein 1 (LMP1) encoded by Epstein-Barr virus induces expression of the putative oncogene Bcl-3 through activation of the nuclear factor-kappaB.
The Epstein-Barr virus (EBV)-encoded oncoprotein latent membrane protein 1 (LMP1) has an essential role in B-lymphocyte transformation by the virus and is expressed in certain EBV-associated tumors and lymphoproliferative disorders. By using the Flp-In/TREx-inducible expression system, we introduced LMP1 into two human cell lines, Jurkat and HEK-293, and found that in both of them the putative cellular oncogene Bcl-3 is rapidly induced following the expression of LMP1. Bcl-3 was also induced in Ramos cells after in vitro EBV infection and after transfection with an LMP1 expression vector. This LMP1-induced Bcl-3 expression is considered to be mediated by the transcription factor NF-kappaB, because (1) deletion of a critical NF-kappaB-binding site in the Bcl-3 promoter abolished its responsiveness to LMP1, (2) an IkappaB mutant that specifically inhibits NF-kappaB activity suppressed the LMP1-induced activation of the Bcl-3 promoter, and (3) an LMP1 mutant lacking its effector domain CTAR2, required for the activation of NF-kappaB, is severely impaired in its ability to induce Bcl-3. Western blot analyses showed that all EBV-infected and LMP1-expressing lymphoid cell lines express Bcl-3. These results suggest the possibility that Bcl-3 is involved in the pathogenesis of certain EBV-associated malignancies and lymphoproliferative disorders.
Nakamura
Hiroyuki
H
Department of Infectious Diseases, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
Ishii
Chihiro
C
Suehiro
Masakazu
M
Iguchi
Akifumi
A
Kuroda
Kazumichi
K
Shimizu
Kazufumi
K
Shimizu
Norio
N
Imadome
Ken-Ichi
K
Yajima
Misako
M
Fujiwara
Shigeyoshi
S
D000081242:B-Cell Lymphoma 3 Protein; D001665:Binding Sites; D015153:Blotting, Western; D002460:Cell Line; D017930:Genes, Reporter; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D014763:Viral Matrix Proteins; D008156:Luciferases