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

Diana Tacelosky,Douglas Dluzen,David X. Liu,Matthew Moreau,Guangfu Li

doi:10.1074/jbc.m110.207639

Diana Tacelosky, Douglas Dluzen + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m110.207639

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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.

Highlights

By serum withdrawal and in FL5.12 cells, an IL-3-dependent cell line, by IL-3 deprivation [8]
To ascertain that ATF5 downregulation is not restricted to cell death provoked by serum deprivation (SD) but instead is a more general response in apoptotic cells, we analyzed ATF5 expression in C6 and MCF-7 cells subjected to additional apoptotic stimuli
These data demonstrate that ATF5 is down-regulated in C6 and MCF-7 cells subjected to a variety of apoptotic stimuli, which is consistent with an earlier report showing that ATF5 is downregulated in growth factor-deprived FL5.12 and HT-2 cells [8]

Summary

Introduction

By serum withdrawal and in FL5.12 cells, an IL-3-dependent cell line, by IL-3 deprivation [8]. BCL-2 Is Regulated by ATF5 in C6 and MCF-7 Cells—To examine whether expression of the endogenous BCL-2 transcript is regulated by ATF5 activity, we performed QRT-PCR analysis on BCL-2 mRNA in C6 cells infected with empty retroviruses or retroviruses expressing wtATF5 or dnATF5.

Results

Conclusion