Bcl-2 is an apoptotic target suppressed by both c-Myc and E2F-1

Malignant transformation occurs in cells that overexpress c-Myc or that ina ppropriately activate E2F-1. Transformation occurs after the selection of c ells that have acquired resistance to apoptosis that is triggered by these oncogenes, and a key mediator of this cell death process is the p53 tumor s uppressor. In IL-3-dependent immortal 32D.3 myeloid cells the ARF/p53 apopt otic pathway is inactivated, as these cells fail to express ARF. Nonetheles s, both c-Myc and E2F-1 overexpression accelerated apoptosis when these cel ls were deprived of IL-3. Here we report that c-Myc or E2F-1 overexpression suppresses Bcl-2 protein and RNA levels, and that restoration of Bcl-2 pro tein effectively blocks the accelerated apoptosis that occurs when c-Myc- o r E2F-1-overexpressing cells are deprived of IL-3. Blocking p53 activity wi th mutant p53 did not abrogate E2F-1-induced suppression of Bcl-2. Analysis of immortal myeloid cells engineered to overexpress c-Myc and E2F-1 DNA bi nding mutants revealed that DNA binding activity of these oncoproteins is r equired to suppress Bcl-2 expression. These results suggest that the target ing of Bcl-2 family members is an important mechanism of oncogene-induced a poptosis, and that this occurs independent of the ARF/p53 pathway.