AATF mediates an antiapoptotic effect of the unfolded protein response through transcriptional regulation of AKT1
Program in Gene Function and Expression; Program in Molecular Medicine; Department of Medicine, Division of Diabetes
Medical Subject Headings
Animals; Apoptosis; Calmodulin-Binding Proteins; Cell Line; Cell Line, Tumor; Cells, Cultured; Chromatin Immunoprecipitation; Humans; Immunoblotting; Immunoprecipitation; In Situ Nick-End Labeling; Lentivirus; Membrane Proteins; Mice; Mice, Inbred C57BL; Models, Biological; Oligonucleotide Array Sequence Analysis; Protein Binding; Proto-Oncogene Proteins c-akt; Rats; STAT3 Transcription Factor; Transcription Factors
Cell and Developmental Biology | Life Sciences | Medicine and Health Sciences
Endoplasmic reticulum (ER) stress-mediated cell death has an important role in the pathogenesis of chronic diseases, including diabetes and neurodegeneration. Although proapoptotic programs activated by ER stress have been extensively studied, identification and characterization of antiapoptotic programs that counteract ER stress are currently incomplete. Through the gene expression profiling of beta-cells lacking Wolfram syndrome 1 gene (WFS1), a causative gene for Wolfram syndrome, we discovered a novel antiapoptotic gene of the unfolded protein response (UPR), apoptosis antagonizing transcription factor (AATF). Here, we study the regulation of AATF, identify its target genes, and determine the basis for its antiapoptotic activities in response to ER stress. We show that AATF is induced by ER stress through the PERK-eIF2alpha pathway and transcriptionally activates the v-akt murine thymoma viral oncogene homolog 1 (AKT1) gene through signal transducer and activator of transcription 3 (Stat3), which sustains Akt1 activation and promotes cell survival. Ectopic expression of AATF or a constitutively active form of AKT1 confers on cells resistance to ER stress-mediated cell death, whereas RNAi-mediated knockdown of AATF or AKT1 renders cells sensitive to ER stress. We also discovered a positive crosstalk between the AATF and WFS1 signaling pathways. Thus, WFS1 deficiency or AATF deficiency mediates a self-perpetuating cycle of cell death. Our results reveal a novel antiapoptotic program relevant to the treatment of diseases caused by ER stress-mediated cell death.
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Citation: Cell Death and Differentiation (2010) 17, 774–786; doi:10.1038/cdd.2009.175; published online 13 November 2009