Show simple item record

dc.contributor.authorIshigaki, Shinsuke
dc.contributor.authorFonseca, Sonya G.
dc.contributor.authorOslowski, Christine M.
dc.contributor.authorJurczyk, Agata
dc.contributor.authorShearstone, Jeffrey R.
dc.contributor.authorZhu, Lihua Julie
dc.contributor.authorPermutt, M. A.
dc.contributor.authorGreiner, Dale L.
dc.contributor.authorUrano, Fumihiko
dc.contributor.authorBortell, Rita
dc.date2022-08-11T08:08:53.000
dc.date.accessioned2022-08-23T16:11:14Z
dc.date.available2022-08-23T16:11:14Z
dc.date.issued2010-05-01
dc.date.submitted2010-09-23
dc.identifier.citationCell Death and Differentiation (2010) 17, 774–786; doi:10.1038/cdd.2009.175; published online 13 November 2009
dc.identifier.issn1476-5403
dc.identifier.doi10.1038/cdd.2009.175
dc.identifier.pmid19911006
dc.identifier.urihttp://hdl.handle.net/20.500.14038/33116
dc.description.abstractEndoplasmic 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=19911006&dopt=Abstract">Link to article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1038/cdd.2009.175
dc.subjectAnimals; 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
dc.subjectCell and Developmental Biology
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleAATF mediates an antiapoptotic effect of the unfolded protein response through transcriptional regulation of AKT1
dc.typeJournal Article
dc.source.journaltitleCell death and differentiation
dc.source.volume17
dc.source.issue5
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/1659
dc.identifier.contextkey1578324
html.description.abstract<p>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.</p>
dc.identifier.submissionpathgsbs_sp/1659
dc.contributor.departmentDepartment of Medicine, Division of Diabetes
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentProgram in Gene Function and Expression
dc.source.pages774–786
dc.contributor.studentJeffrey R. Shearstone; Sonya G. Fonseca


This item appears in the following Collection(s)

Show simple item record