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 functional homolog of the Bcl-2 protein. Both BHRF1 and Bcl-2 proteins promote 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 contribute to oncogenesis merely by promoting cell survival. We have discovered that mutations within a regulatory domain of the BHRF1 protein not only suppress apoptosis induced by the tumor suppressor protein p53, but also permit efficient proliferation of cells that would otherwise undergo total apoptosis. These gain-of-function mutants of BHRF1 cooperate more efficiently with the E1a oncogene in transformation of primary rat kidney cells where E1A expression results in apoptosis. Our results suggest that such mutational inactivation of a proliferation-restraining activity in the BHRF1 gene may play a direct role in oncogenesis.