The Epstein-Barr virus gene BHRF1, a homologue of the cellular oncogene Bcl-2, inhibits apoptosis induced by gamma radiation and chemotherapeutic drugs.
Analysis of apoptosis, active and controllable cell death, has demonstrated that the size of a cell population can be regulated by changes in the cell death rate as well as in the rates of proliferation and differentiation. Factors which alter the rate of cell death, such as expression of the proto-oncogene bcl-2, can therefore directly affect the number of cells within a population. Bcl-2 has been shown to suppress apoptosis in response to a variety of stimuli and to act as a complementary survival signal for the random acquisition of other oncogenic mutations, such as deregulated c-myc. The Epstein Barr virus (EBV) gene BHRF1 was the first of a family of bcl-2 homologues now being identified. BHRF1 and bcl-2 share 25% primary amino acid sequence homology. Here we show that gamma radiation and several cytotoxic anticancer agents induce apoptosis in Burkitt's lymphoma (BL) cell lines, as has been found in several other systems. Using gene transfection studies we have also shown that expression of either BHRF1 or bcl-2 in BL cell lines significantly suppresses apoptosis in response to a variety of anticancer treatment. This has confirmed that BHRF1 is functionally homologous to bcl-2 in B-cells and suggests that BHRF1 may act to prevent apoptosis during EBV infection, maximising virus particle production, as has been suggested for other human and insect viral genes. Suppression of chemotherapeutic drug induced cell death by bcl-2 and BHRF1 as demonstrated in this cell system, results in resistance to a variety of different agents and may represent an alternative mechanism by which multidrug resistance arises during chemotherapy.
Department of Biological Sciences Keele University, Staffordshire, United Kingdom.
N J
NJ
McCarthy
S A
SA
Hazlewood
D S
DS
Huen
A B
AB
Rickinson
G T
GT
Williams
D017209:Apoptosis / Q000502:physiology*; D004358:Drug Therapy; D005720:Gamma Rays; D016153:Genes, Suppressor; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000235:genetics*
C083278:BHRF1 protein, Human herpesvirus 4; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D014764:Viral Proteins