THE ANTI-APOPTOSIS FUNCTION OF BCL-2 CAN BE GENETICALLY SEPARATED FROM ITS INHIBITORY EFFECT ON CELL-CYCLE ENTRY

The Bcl-2 family of proteins regulate apoptosis, some antagonizing cel l death and others facilitating it, It has recently been demonstrated that Bcl-2 not only inhibits apoptosis but also restrains cell cycle e ntry, We show here that these two functions can be genetically dissoci ated, Mutation of a tyrosine residue within the conserved N-terminal B H4 region had no effect on the ability of Bcl-2 or its closest homolog s to enhance cell survival and did not prevent heterodimerization with death-enhancing family members Bar, Bah, Bad and Bik. Neither did thi s mutation override the growth-inhibitory effect of p53, However, on s timulation with cytokine or serum, starved quiescent cells expressing the mutant proteins re-entered the cell cycle much faster than those e xpressing comparable levels of wildtype proteins. When wild-type and Y 28 mutant Bcl-2 were co-expressed, the mutant was dominant, Although R -Ras p23 has been reported to bind to Bcl-2, no interaction was detect able in transfected cells and R-Ras p23 did not interfere with the abi lity of Bcl-2 to inhibit apoptosis or cell cycle entry, These observat ions provide evidence that the anti-apoptotic function of Bcl-2 is mec hanistically distinct from its inhibitory influence on cell cycle entr y.