title: miR-216b regulation of c-Jun mediates GADD153/CHOP-dependent apoptosis.
abstract: The ability of the unfolded protein response, UPR, to regulate cell homeostasis through both gene expression and protein synthesis has been well documented. One primary pro-apoptotic protein that responds to both PERK and Ire1 signalling is the CHOP/GADD153 transcription factor. Although CHOP deficiency delays onset of cell death, questions remain regarding how CHOP regulates apoptosis. Here, we provide evidence demonstrating that CHOP/GADD153-dependent apoptosis reflects expression of micro-RNA, miR-216b. MiR-216b accumulation requires PERK-dependent induction of CHOP/GADD153, which then directly regulates miR-216b expression. As maximal expression of miR-216b is antagonized by Ire1, miR-216b accumulation reflects the convergence of PERK and Ire1 activities. Functionally, miR-216b directly targets c-Jun, thereby reducing AP-1-dependent transcription and sensitizing cells to ER stress-dependent apoptosis. These results provide direct insight into the molecular mechanisms of CHOP/GADD153-dependent cell death.
authors.affiliation: Department of Biochemistry, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, 3400, Charleston, South Carolina 29425, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Biochemistry, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, 3400, Charleston, South Carolina 29425, USA.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Bu
authors.affiliation: Department of Biochemistry, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, 3400, Charleston, South Carolina 29425, USA.
authors.forename: Nilesh
authors.initials: N
authors.lastname: Chitnis
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Costas
authors.initials: C
authors.lastname: Koumenis
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, 380 S. University Avenue, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
authors.affiliation: Department of Biochemistry, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, 3400, Charleston, South Carolina 29425, USA.
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: C497249:DDIT3 protein, human; C575482:MIRN216 microRNA, human; D035683:MicroRNAs; D016755:Proto-Oncogene Proteins c-jun; D051742:Transcription Factor CHOP; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases