BCL-2 Is a Downstream Target of ATF5 That Mediates the Prosurvival Function of ATF5 in a Cell Type-dependent Manner

Abstract

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.ATF5 (activating transcription factor 5; also known as ATFx) is a member of the ATF/cAMP response element-binding protein (CREB) 2 family of bZIP (basic zipper) proteins (1). It can bind to several transcription regulatory DNA elements that include cAMP response elements (CRE), an amino acid response element, and an ATF5-specific response element (ARE) and regulate gene expression in different types of cells (1-4). ATF5 has been identified as a factor whose down-regulation is essential for differentiation of rat neural progenitor cells and PC12 pheochromocytoma cells (5-7). ATF5 is expressed in a number of cancer cells and down-regulated in those cells following growth factor deprivation; exogenous expression of ATF5 suppresses apoptosis in HeLa cells induced by serum withdrawal and in FL5.12 cells, an IL-3-dependent cell line, by IL-3 deprivation (8). Conversely, dominant-negative ATF5 induces apoptosis of HeLa and FL5.12 cells and a number of glioma and breast cancer cell lines cultured in the presence of growth factors (8 -10). Similar interference of ATF5 function in non-neoplastic breast cells or in non-tumor brain cells, such as mature neurons and glial cells, does not affect their survival (9, 10). The mechanism of such selective survival requirement for ATF5 in different cell types is not understood.The BCL-2 family of proteins includes both anti-apoptotic (BCL-2, BCL-X L , and MCL-1) and apoptotic (BAK, BAX, BID, and BIM) proteins. The regulation and balance of this BCL-2 family of proteins in a particular cell result in inhibition or induction of the apoptotic signaling pathways (11,12). Notably, the expression pattern ...

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