Diminished Cell Proliferation Associated with the Death-protective Activity of Bcl-2*

Abstract

The oncogene product Bcl-2 effectively spares cells from programmed cell death (apoptosis). The molecular mechanism underlying this death-protective activity has, however, remained enigmatic. Here we show that induction of Bcl-2 expression is consistently associated with a retardation of mammalian cell proliferation due to a prolongation of the G₁ phase of the cell cycle. Whereas cells lacking Bcl-2 expression die from any point of the cell cycle in response to apoptotic agents, Bcl-2-overexpressing cells accumulate in the G₀/G₁ phase and are protected from cell death. Co-expression of Bax, a negative regulator of Bcl-2, reverts both the cell death protective and proliferation retarding activities of Bcl-2. Moreover, a Bcl-2 mutant defective in death protection does not affect cell division. These findings indicate that Bcl-2 contributes to cell survival by diminishing the rate of cell proliferation.