title: The ability of BHRF1 to inhibit apoptosis is dependent on stimulus and cell type.
abstract: The development of resistance to host defense mechanisms such as tumor necrosis factor (TNF)- and Fas-mediated apoptosis of transformed or virus-infected cells may be a critical component in the development of disease. To find genes that protect cells from apoptosis, we used an expression cloning strategy and identified BHRF1, an Epstein-Barr virus (EBV) early-lytic-cycle protein with distant homology to Bcl-2, as an anti-apoptosis protein. Expression of BHRF1 in MCF-Fas cells conferred nearly complete resistance against both anti-Fas antibody and TNF-mediated apoptosis. In addition, BHRF1 protected these cells from monocyte-mediated killing but failed to protect them from killing mediated by lymphokine-activated killer cells. The ability of BHRF1 to protect MCF-Fas cells from apoptosis induced by various stimuli was identical to that of Bcl-2 and Bcl-xL. Moreover, the mechanism of action of BHRF1 resembled that of Bcl-2 and Bcl-xL as it inhibited TNF- and anti-Fas-induced activation of two enzymes participating in the apoptosis pathway, cytosolic phospholipase A2 and caspase-3/CPP32, but did not interfere with the activation of NF-kappaB-like transcription factors. A putative function of BHRF1 in EBV-infected epithelial cells may be to protect virus-infected cells from TNF- and/or anti-Fas-induced cell death in order to maximize virus production. Surprisingly, expression of neither BHRF1 nor Bcl-2 in a B-cell line, BJAB, protected the cells from anti-Fas-mediated apoptosis even though they increased the survival of serum-starved cells. Thus, the protective role of BHRF1 against apoptosis resembles that of Bcl-2 in being cell type specific and dependent on the apoptotic stimulus.
authors.affiliation: Division for Cancer Biology, Danish Cancer Society, Copenhagen.
authors.forename: L
authors.initials: L
authors.lastname: Foghsgaard
authors.forename: M
authors.initials: M
authors.lastname: Jäättelä
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms; D053148:Caspase 3; D020169:Caspases; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D002999:Clone Cells; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D018274:Electroporation; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D015723:Gene Library; D017930:Genes, Reporter; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis; D008214:Lymphocytes / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014764:Viral Proteins / Q000096:biosynthesis / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology
chemical_list: C083278:BHRF1 protein, Human herpesvirus 4; D004792:Enzyme Precursors; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D019014:fas Receptor; D008156:Luciferases; D010741:Phospholipases A; D054467:Phospholipases A2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases