BCL-2 is a downstream target of ATF5 that mediates the prosurvival function of ATF5 in a cell type-dependent manner

ATF5 loss of function has been shown previously to cause apoptotic cell death in glioblastoma and breast Cancer cells but not in non-transformed astrocytes and human breast epithelial cells. The mechanism for the cell type-dependent survival function of ATF5 is unknown. We report here that the anti-apoptotic factor Bcl-2 is a downstream target of ATF5 that mediates the prosurvival function of ATF5 in C6 glioma cells and MCF-7 breast Cancer cells. ATF5 binds to an ATF5-specific regulatory element that is downstream of and adjacent to the negative regulatory element in the Bcl-2 P2 promoter, stimulating Bcl-2 expression. Highlighting the critical role of Bcl-2 in ATF5-dependent Cancer cell survival, expression of Bcl-2 blocks death of C6 and MCF-7 cells induced by dominant-negative ATF5, and depletion of Bcl-2 impairs ATF5-promoted cell survival. Moreover, we found that Bcl-2 expression is not regulated by ATF5 in non-transformed rat astrocytes, mouse embryonic fibroblasts, and human breast epithelial cells, where expression of Bcl-2 but not ATF5 is required for cell survival. These findings identify Bcl-2 as an essential mediator for the cancer-specific cell survival function of ATF5 in glioblastoma and breast Cancer cells and provide direct evidence that the cell type-specific function of ATF5 derives from differential regulation of downstream targets by ATF5 in different types of cells.