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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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Submitted July 19, 2004
Accepted December 11, 2004
EBV latent membrane protein-1 protects B-cells from apoptosis by inhibition of bax
Thomas Grimm, Sabine Schneider, Elisabeth Naschberger, Jurgen Huber, Eric Guenzi, Arnd Kieser, Peter Reitmeir, Thomas F Schulz, Cindy A Morris, and Michael Sturzl*
Department of Virus-induced Vasculopathy, GSF-National Research Center for Environment and Health, Institute of Molecular Virology, Neuherberg, Germany
Department of Surgery, Division of Molecular and Experimental Surgery, University of Erlangen-Nurnberg, Erlangen, Germany
Department of Gene Vectors, GSF-National Research Center for Environment and Health, Institute of Clinical Molecular Biology and Tumor Genetics, Munich, Germany
Institute of Health Economics and Health Care Management, GSF-National Research Center for Environment and Health, Neuherberg, Germany
Department of Virology, Medical School Hannover, Hannover, Germany
Department of Microbiology and Immunology, Tulane University Health Service Center, New Orleans, LA, USA
Department of Virus-induced Vasculopathy, GSF-National Research Center for Environment and Health, Institute of Molecular Virology, Neuherberg, Germany; Department of Surgery, Division of Molecular and Experimental Surgery, University of Erlangen-Nurnberg, Erlangen, Germany
* Corresponding author; email: michael.stuerzl{at}chir.imed.uni-erlangen.de.
Latent membrane protein (LMP)-1 of Epstein-Barr virus (EBV) promotes tumorigenesis by inhibiting apoptosis. We show that an important anti-apoptotic activity of LMP-1 is the inhibition of Bax, a potent pro-apoptotic protein. Bax expression was regulated by LMP-1 activation of NF- B via the C-terminal activation regions (CTARs) -1 and -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 two of the three NF-kB 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 kB3 site for its activation. However, the activation of the bax promoter by LMP-1 was only observed in the presence of specific inhibitors of p65/p50. In all other cases LMP-1 inhibited bax promoter activity. Most importantly, the anti-apoptotic activity of LMP-1 was considerably decreased in cells deficient for bax. These results indicate that the inhibition of bax may be an important anti-apoptotic activity of LMP-1.
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