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Journal of Virology, July 2000, p. 6652-6658, Vol. 74, No. 14
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
The bfl-1 Gene Is Transcriptionally Upregulated by the
Epstein-Barr Virus LMP1, and Its Expression Promotes the Survival
of a Burkitt's Lymphoma Cell Line
Brendan
D'Souza,1
Martin
Rowe,2 and
Dermot
Walls1,*
School of Biotechnology, Dublin City
University, Dublin 9, Ireland,1 and
Department of Medicine, University of Wales College of
Medicine, Cardiff CF14 4XX, United Kingdom2
Received 12 January 2000/Accepted 17 April 2000
The recently identified bfl-1 gene (also known as
A1 or GRS), a homologue of bcl-2,
encodes an antiapoptotic protein that suppresses
apoptosis induced by the p53 tumor suppressor protein and
exhibits proliferative and potent cooperative transforming activities.
We show that elevated levels of bfl-1 mRNA are a feature of Epstein-Barr virus (EBV)-immortalized B-cell lines and
Burkitt's lymphoma cell lines expressing the full spectrum of EBV
latent proteins. Using an EBV-negative Burkitt's lymphoma cell line in which the expression of EBV latent membrane protein 1 (LMP1) is inducibly regulated by tetracycline, we demonstrate that LMP1 expression coincides with a dramatic increase in the level of bfl-1 mRNA. Also in this system, an increase in the level
of Bcl-2 protein was seen to occur earlier than that of
bcl-2 mRNA, suggesting that both transcriptional and
translational mechanisms are involved in the control of Bcl-2
expression by LMP-1. We show that elevated bfl-1
mRNA stability can contribute to this effect of LMP-1, thus providing evidence of a novel mechanism of gene
regulation by this EBV protein. Upregulation of
bfl-1 by LMP1 was not observed in the T-cell line Jurkat
or the epithelial cell line C33A. Ectopic expression of Bfl-1 in an EBV-positive cell line exhibiting a latency
type I infection protects against apoptosis induced by growth factor deprivation, thereby providing a functional role for
Bfl-1 in this cellular context and adding Bfl-1 to the list of
antiapoptotic proteins whose expression is modulated by EBV. This is the first report of the regulation of bfl-1
expression by a viral protein, and this novel finding may thus
represent an important link between the EBV oncoprotein LMP1 and its
cellular growth-transforming properties.
*
Corresponding author. Mailing address: School of
Biotechnology, Dublin City University, Dublin 9, Ireland. Phone:
353.1.7045600. Fax: 353.1.7045412. E-mail:
Dermot.Walls{at}dcu.ie.
Journal of Virology, July 2000, p. 6652-6658, Vol. 74, No. 14
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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