title: miR-211 is a prosurvival microRNA that regulates chop expression in a PERK-dependent manner.
abstract: MicroRNAs typically function at the level of posttranscriptional gene silencing within the cytoplasm; however, increasing evidence suggests that they may also function in nuclear, Argonaut-containing complexes, to directly repress target gene transcription. We have investigated the role of microRNAs in mediating endoplasmic reticulum (ER) stress responses. ER stress triggers the activation of three signaling molecules: Ire-1α/β, PERK, and ATF6, whose function is to facilitate adaption to the ensuing stress. We demonstrate that PERK induces miR-211, which in turn attenuates stress-dependent expression of the proapoptotic transcription factor chop/gadd153. MiR-211 directly targets the proximal chop/gadd153 promoter, where it increases histone methylation and represses chop expression. Maximal chop accumulation ultimately correlates with miR-211 downregulation. Our data suggest a model in which PERK-dependent miR-211 induction prevents premature chop accumulation and thereby provides a window of opportunity for the cell to re-establish homeostasis prior to apoptotic commitment.
authors.affiliation: The Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Nilesh S
authors.initials: NS
authors.lastname: Chitnis
authors.forename: Dariusz
authors.initials: D
authors.lastname: Pytel
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Bobrovnikova-Marjon
authors.forename: Dhruv
authors.initials: D
authors.lastname: Pant
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Maas
authors.forename: Brian
authors.initials: B
authors.lastname: Frederick
authors.forename: Jake A
authors.initials: JA
authors.lastname: Kushner
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Chodosh
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics* / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D004268:DNA-Binding Proteins; D006657:Histones; D035683:MicroRNAs; D019284:Thapsigargin; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D019892:eIF-2 Kinase; C081452:Atf4 protein, mouse; C497250:Ddit3 protein, mouse; C103652:Elf2 protein, mouse; C577982:Mirn211 microRNA, mouse