Epstein-Barr virus latent membrane protein 1 blocks p53-mediated apoptosis through the induction of the A20 gene.
Two Epstein-Barr virus (EBV)-associated malignancies, nasopharyngeal carcinoma and posttransplant lymphoma, rarely have mutations in the p53 tumor suppressor gene, suggesting that a viral protein interferes with p53 function. The EBV oncogene, LMP1, induces expression of the cellular antiapoptotic genes bcl-2 and A20 and could in this way interfere with p53-mediated apoptosis. Two derivatives of the p53-null epithelial cell line H1299 were prepared, one of which (H1299-p53) stably expressed a temperature-sensitive (ts) p53 protein, and another (H1299-p53+LMP1) which stably expressed both ts-p53 and latent membrane protein 1 (LMP1). At the permissive temperature, the p53 protein in the H1299-p53 cell line transcriptionally activated two of its target genes, the cyclin-dependent kinase inhibitor p21 and the mdm2 gene product, in an LMP1-independent manner. Upon serum withdrawal at the permissive temperature, p53-mediated apoptosis was induced in 50 to 60% of the cells. In the H1299-p53 cell line which stably expressed LMP1, however, only 20 to 25% of the cells underwent apoptosis. While stable expression of LMP1 did not affect levels of bcl-2 family members in these cells, it did induce expression of A20. Stable expression of A20 in the H1299-p53 cell line inhibited p53-mediated apoptosis equivalent to inhibition by LMP1. The induction of A20 may underlie the ability of LMP1 to protect EBV-infected epithelial cells from p53-mediated apoptosis.
Fries
K L
KL
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, 27599-7295, USA.
Miller
W E
WE
Raab-Traub
N
N
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D016296:Mutagenesis; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D014763:Viral Matrix Proteins; D051020:bcl-X Protein; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)