title: Identification of a novel endoplasmic reticulum stress response element regulated by XBP1.
abstract: Understanding the regulatory mechanisms mediating PRNP gene expression is highly relevant to elucidating normal cellular prion protein (PrP) function(s) and the transmissibility of prion protein neurodegenerative diseases. Here, luciferase reporter assays showed that an endoplasmic reticulum stress element (ERSE)-like element, CCAAT-N26-CCACG in the human PRNP promoter, is regulated by ER stress and X-box-binding protein 1 (XBP1) but not by activating transcription factor 6 α (ATF6α). Bioinformatics identified the ERSE-26 motif in 37 other human genes in the absence of canonical ERSE sites except for three genes. Several of these genes are associated with a synaptic function or are involved in oxidative stress. Brefeldin A, tunicamycin, and thapsigargin ER stressors induced gene expression of PRNP and four randomly chosen ERSE-26-containing genes, ERLEC1, GADD45B, SESN2, and SLC38A5, in primary human neuron cultures or in the breast carcinoma MCF-7 cell line, although the level of the response depends on the gene analyzed, the genetic background of the cells, the cell type, and the ER stressor. Overexpression of XBP1 increased, whereas siRNA knockdown of XBP1 considerably reduced, PRNP and ERLEC1 mRNA levels in MCF-7 cells. Taken together, these results identify a novel ER stress regulator, which implicates the ER stress response in previously unrecognized cellular functions.
authors.affiliation: Department of Anatomy and Cell Biology, McGill University, Montreal, Québec H3T 1E2, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Misiewicz
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Déry
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Foveau
authors.forename: Julie
authors.initials: J
authors.lastname: Jodoin
authors.forename: Derek
authors.initials: D
authors.lastname: Ruths
authors.forename: Andréa C
authors.initials: AC
authors.lastname: LeBlanc
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics; D000943:Antigens, Differentiation / Q000235:genetics; D001483:Base Sequence; D015153:Blotting, Western; D020126:Brefeldin A / Q000494:pharmacology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D037102:Lectins / Q000235:genetics; D061986:MCF-7 Cells; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D059372:Nucleotide Motifs / Q000235:genetics; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology; D000071717:X-Box Binding Protein 1; D000097642:GADD45 Proteins; D000084622:Sestrins
chemical_list: D051702:Activating Transcription Factor 6; D026921:Amino Acid Transport Systems, Neutral; D000943:Antigens, Differentiation; D020126:Brefeldin A; D004268:DNA-Binding Proteins; D037102:Lectins; D009687:Nuclear Proteins; D000072002:Prion Proteins; D011328:Prions; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D019284:Thapsigargin; D014157:Transcription Factors; D014415:Tunicamycin; D000071717:X-Box Binding Protein 1; C531192:ERLEC1 protein, human; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C512656:PRNP protein, human; C465398:SESN2 protein, human; D000084622:Sestrins; C424137:SLC38A5 protein, human; C000605543:XBP1 protein, human
keywords: ER Stress; ERSE; Endoplasmic Reticulum Stress; Gene Regulation; Gene Transcription; Prions; XBP-1