title: 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.
authors.affiliation: Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Dluzen
authors.forename: Guangfu
authors.initials: G
authors.lastname: Li
authors.forename: Diana
authors.initials: D
authors.lastname: Tacelosky
authors.forename: Matthew
authors.initials: M
authors.lastname: Moreau
authors.forename: David X
authors.initials: DX
authors.lastname: Liu
mesh_terms: D051696:Activating Transcription Factors / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005910:Glioma; D006801:Humans; D011401:Promoter Regions, Genetic / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C507532:ATF5 protein, human; D051696:Activating Transcription Factors; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D019311:Staurosporine