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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3263-3269.
Prepublished online as a Blood First Edition Paper on December 21, 2004; DOI 10.1182/blood-2004-07-2752.
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NEOPLASIA
EBV latent membrane protein-1 protects B cells from apoptosis by inhibition of BAX
Thomas Grimm,
Sabine Schneider,
Elisabeth Naschberger,
Jürgen Huber,
Eric Guenzi,
Arnd Kieser,
Peter Reitmeir,
Thomas F. Schulz,
Cindy A. Morris, and
Michael Stürzl
From the University of Erlangen-Nürnberg, Department of Surgery, Division of Molecular and Experimental Surgery, Erlangen, Germany; the GSF-National Research Center for Environment and Health, Institute of Molecular Virology, Department of Virus-induced Vasculopathy, and the Institute of Health Economics and Health Care Management, Neuherberg, Germany; GSF-National Research Center for Environment and Health, Institute of Clinical Molecular Biology and Tumor Genetics, Department of Gene Vectors, Munich, Germany; Medical School Hannover, Department of Virology, Hannover, Germany; and Tulane University Health Service Center, Department of Microbiology and Immunology, New Orleans, LA.
Latent membrane protein 1 (LMP-1) of Epstein-Barr virus (EBV) promotes tumorigenesis by inhibiting apoptosis. We show that an important antiapoptotic activity of LMP-1 is the inhibition of Bcl2-associated protein X (Bax), a potent proapoptotic protein. BAX expression was regulated by LMP-1 activation of nuclear factor  B (NF-B) via the C-terminal activation region 1 (CTAR-1) and CTAR-2. Interestingly, p65/p50 inhibited, whereas p50/p50 increased, BAX promoter activity as demonstrated by overexpression and selective inhibition of these NF-B isoforms. Electrophoretic mobility shift analysis revealed that LMP-1 activates 2 of the 3 NF-B binding sites (B1-B3) in the BAX promoter. LMP-1 induced binding of the NF-B heterodimer p65/p50 to the B2 site and of the p50/p50 homodimer to the B3 site. Promoter mutation analysis revealed that the B2 site is necessary for inhibition of BAX promoter activity and the B3 site, for its activation. However, the activation of the BAX promoter by LMP-1 was observed only in the presence of specific inhibitors of p65/p50. In all other cases, LMP-1 inhibited BAX promoter activity. Most importantly, the antiapoptotic activity of LMP-1 was considerably decreased in cells deficient for BAX. These results indicate that the inhibition of Bax may be an important antiapoptotic activity of LMP-1. (Blood. 2005;105:3263-3269)
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