UNMASKING OF A PROLIFERATION-RESTRAINING ACTIVITY OF THE ANTI-APOPTOSIS PROTEIN EBV BHRF1

The BHRF1 protein of Epstein-Barr virus (EBV) is a structural and func tional homolog of the Bcl-2 protein, Both BHRF1 and Bcl-2 proteins pro mote the survival of cells exposed to various apoptotic stimuli. This promotion of cell survival is associated with a block in proliferation , It is believed that the Bcl-2 family of anti-apoptosis proteins cont ribute to oncogenesis merely by promoting cell survival. We have disco vered that mutations within a regulatory domain of the BHRF1 protein n ot only suppress apoptosis induced by the tumor suppressor protein p53 , but also permit efficient proliferation of cells that would otherwis e undergo total apoptosis, These gain-of-function mutants of BHRF1 coo perate more efficiently with the E1a oncogene in transformation of pri mary rat kidney cells where E1A expression results in apoptosis. Our r esults suggest that such mutational inactivation of a proliferation-re straining activity in the BHRF1 gene may play a direct role in oncogen esis.