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Hypothermia Regulates Endoplasmic Reticulum (ER) Stress through the X-box Binding Protein-1 (XBP1) Gene Expression in PC12 Cells
Biomed Sci Letters 2017;23:416-420
Published online December 31, 2017;  https://doi.org/10.15616/BSL.2017.23.4.416
© 2017 The Korean Society For Biomedical Laboratory Sciences.

Bo-Kyung Yoo1,¦, Kisang Kwon2,¦, Eun Ryeong Lee2, and O-Yu Kwon1,†

1Department of Anatomy & Cell Biology, College of Medicine, Chungnam National University, Daejeon 35015, Korea,
2Department of Biomedical Laboratory Science, College of Health & Welfare, Kyungwoon University, Gumi 39160, Korea
Correspondence to: O-Yu Kwon. Department of Anatomy & Cell Biology, College of Medicine, Chungnam National University, Daejeon 35015, Korea. Tel: +82-42-580-8206, Fax: +82-42-586-4800, e-mail: oykwon@cnu.ac.kr
Received October 20, 2017; Revised November 25, 2017; Accepted December 8, 2017.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract

Endoplasmic reticulum (ER) stress induces unfolded protein response (UPR) via inositol-requiring enzyme 1 (IRE1) activation, which sends a molecular signal for X box-binding protein 1 (XBP1) mRNA splicing in the cytosol. IRE1 endoribonuclease activity induces cleavage of XBP1 mRNA. The XBP1 mRNA is then ligated by an uncharacterized RNA ligase and translated to produce spliced XBP1 by 23 nt removed in which contains the PstI restriction enzyme site. The splicing of XBP1 mRNA can be detected by semiquantitative RT-PCR, and then splicing of XBP1 is a useful tool to measure the genetic variability in ER stress. In this study, we have estimated IRE1-dependent splicing of XBP1 mRNA under conditions of various hypothermia. The results indicated that hypothermia regulated ER stress. This study demonstrated that hypothermia is closely related to ER stress and may be useful for early diagnosis of ER-associated disease.

Keywords : Hypothermia, Endoplasmic Reticulum (ER) Stress, X-box Binding Protein-1 (XBP1)
Body

吏꾪빑꽭룷뿉꽌 냼룷泥(endoplasmic reticulum: ER)쓽 二쇰맂 깮臾쇳븰쟻 湲곕뒫 떊깮 떒諛깆쭏쓽 踰덉뿭 썑 蹂삎 怨쇱젙(post-translational modification step)쓣 닔뻾븯뒗 寃껋씠떎. 利, 냼룷泥대뒗 mRNA뿉꽌 깉濡寃 留뚮뱾뼱吏 誘몄셿꽦쓽 polypeptide媛 젙긽쟻씤 湲곕뒫쓣 媛吏 遺꾨퉬/留 떒諛깆쭏씠 릺湲 쐞븯뿬 folding & assembly, glycosylation adding & trimming 벑쓽 怨쇱젙쓣 젙솗븯寃 닔뻾븷 닔 엳룄濡 理쒖쟻쓽 議곌굔쓣 젣怨듯븯뒗 꽭룷궡 냼湲곌씠떎(Schwarz and Blower, 2016). 씠 媛숈 湲곕뒫쓣 以묒텛쟻쑝濡 닔뻾븯뒗 ER lumen뿉 議댁옱븯뒗 떒諛깆쭏臾대━瑜 냼룷泥 遺꾩옄깶럹濡(ER molecular chaperone)씠씪怨 븳떎. 吏湲덇퉴吏 蹂닿퀬맂 몴쟻씤 寃껋쑝濡쒕뒗 binding immunoglobulin protein (BiP), glucose-regulated protein 94(GRP94), endoplasmic reticulum protein (Erp72), protein disulfide isomerase (PDI), calnexin, calreticulin, endoplasmic reticulum 29 (Erp29) 벑씠 엳떎(Hebert and Molinari, 2007; Sontag et al., 2017). 洹몃━怨 냼룷泥닿 젙긽쟻씤 post-translational modification step쓽 솚寃쎌쓣 젣怨듭쓣 쐞븯뿬꽌뒗 꽭룷吏덉뿉 鍮꾪븯뿬 10~100諛 젙룄 넂 移쇱뒛 냽룄媛 sarcoplasmic reticulum Ca2+-ATPase (SERCA)뿉 쓽빐꽌 쑀吏릺뼱빞 븳떎(Periasamy and Kalyanasundaram, 2007). 꽭룷쓽 젙긽쟻씤 湲곕뒫 닔뻾뿉 뿭뻾븯뒗 鍮꾩젙긽쟻씤 꽭룷깮由ы쁽긽씠 냼룷泥댁뿉 吏곸젒쟻쑝濡 臾몄젣瑜 諛쒖깮떆궎硫 吏덈퀝쑝濡 굹궃떎, 씠뱾쓣 珥앷큵븯뿬 ER storage disease (ERSD)씪怨 븳떎(Kim and Arvan, 1998). 吏湲덇퉴吏 蹂닿퀬맂 몴쟻씤 ERSD뒗 꽑泥쒖꽦 媛묒긽꽑 湲곕뒫 븯利(congenital hypothyroidism), 슂遺뺤쬆(diabetes insipidus), 怨⑦삎꽦遺쟾利(osteogenesis imperfect), 吏吏덈궗씠긽(disorders of lipid metabolism, 떦눊蹂(diabetes mellitus)뿉 愿젴맂 40뿬醫낆씠 엳떎. ERSD 媛숈씠 鍮꾩젙긽쟻쑝濡 folding맂 蹂꽦 떒諛깆쭏(malfolded/unfolded/misfolded protein)쓽 異뺤쟻 諛 떒諛깆쭏 assembly媛 굹굹硫, 꽭룷뒗 냼룷泥 뒪듃젅뒪(ER stress)瑜 諛쏅뒗떎. 냼룷泥닿 빑쑝濡 냼룷泥 떊샇쟾떖(ER signal pathway)쓣 넻빐꽌, 꽭룷쓽 쟾泥댁쟻씤 떒諛깆쭏 궗쑉쓣 뼲젣븯뒗 諛⑸쾿怨 냼룷泥 궡뿉 異뺤쟻릺뒗 蹂꽦 떒諛깆쭏쓽 吏곸젒쟻씤 뼲젣, 蹂댄샇 諛 닔蹂듦낵 媛숈 씪쓣 븿쑝濡쒖꽌 꽭룷쓽 homeostasis瑜 쑀吏븯젮怨 븳떎. ER signal pathway뒗 3醫낅쪟쓽 냼룷泥 留 떒諛깆쭏(IRE1: inositol-requiring enzyme 1, PERK: PKR-like ER kinase, ATF6: activating transcription factor 6)뿉 쓽빐꽌 議곗젅맂떎(Back and Kaufman, 2012; Plaquet et al., 2015; Navid and Colbert, 2017). 꽭룷媛 ER stress瑜 諛쏄쾶 릺硫 ER lumen쓽 BiP怨 寃고빀븯怨 엳뜕 monomer 긽깭쓽 IRE1씠 dimmer媛 릺硫댁꽌 X-box binding protein-1 (XBP1) mRNA쓽 splicing씠 씪뼱굹 XBP1 떒諛깆쭏씠 깮궛릺뼱 ER chaperone쓣 깮빀꽦쓣 珥됱쭊븳떎. PERK 뿭떆 monomer 긽깭뿉꽌 ER stress뿉 쓽빐꽌 dimerization릺硫댁꽌 빑쟾궗씤옄씤 eIF2α (eukaryotic initiation factor 2α)媛 씤궛솕媛 씪뼱굹 꽭룷 쟾泥댁쓽 떒諛깆쭏 깮빀꽦쓣 뼲젣븳떎. ATF6 ER stress瑜 諛쏆쑝硫 꽭룷吏 履쎌쓽 떒렪씠 뼥뼱졇 ER stress element (ERSE)뿉 寃고빀븯뿬 ER chaperone쓽 깮빀꽦쓣 珥됱쭊븳떎.

씤泥댁뿉 쟻슜븯뒗 泥댁삩踰(hypothermia treatment) 泥댁삩쓣 35°C 씠븯(씪諛섏쟻쑝濡 32°C)濡 쑀吏븯뿬 諛쒕퀝쓽 吏꾩쟾냽룄瑜 뼲젣븯뒗 寃껉낵 醫뗭 엫긽쟻씤 삁썑瑜 뼸湲 쐞븳 닔떒쑝濡 궗슜릺怨 엳떎(Lee et al., 2017). 媛옣 슚怨쇱쟻씤 泥댁삩踰뺤쓣 American Heart Association쓽 therapeutic hypothermia 媛씠뱶씪씤뿉꽌뒗 32~34°C뿉꽌 12~24떆媛꾩쑝濡 洹쒖젙븯떎(Brooks and Morrison, 2008). 떎젣濡 refractory intracranial hypertension怨 malignant cerebral edema쓽 寃쎌슦뒗 븘二 쑀쓽쟻씤 寃곌낵瑜 뼸뿀떎(Imataka and Arisaka, 2015).鍮꾨줉 泥댁삩踰뺤씠 neurocritical care patient rehabilitation뿉 留롮 옣젏씠 븣젮吏怨 엳吏留 젙솗븳 遺꾩옄닔以쓽 湲곗쟾 紐낇솗븯寃 洹쒕챸릺뼱 엳吏 븡떎(Kwon et al., 2008; Kuroda, 2016). 洹몃윭굹 븘룷넗떆뒪(apoptosis), mitochondrial dysfunction, 뿼利(inflammation), blood-brain barrier disruption, 옄쑀씪뵒移 깮꽦(free radical production), rescue of the RNA-binding motif protein 3 gene 벑씠 蹂닿퀬릺怨 엳떎(Yenari and Zhao, 2003; Yenari and Han, 2012; Guo et al., 2016). 蹂 뿰援ъ뿉꽌뒗 泥댁삩踰 怨쇱젙씠 꽭룷뿉 뼱뼡 쁺뼢쓣 誘몄튂뒗吏瑜 븣湲 쐞븯뿬 ER stress쓽 젙룄瑜 XBP1 mRNA splicing쓣 씠슜븳 RT-PCR濡 솗씤븯떎(Kwon et al., 2005). Fig. 1쓽 紐⑥떇룄뿉꽌 蹂대뒗 寃껉낵 媛숈씠, ER stress뿉 쓽빐꽌 IRE1 dimerization쓣 넻빐꽌 XBP1 mRNA splicing씠 씪뼱굹硫 媛슫뜲 遺遺꾩쓽 23 nt 떒렪씠 젣嫄곕맂떎. 씠 떒렪냽뿉 젣븳슚냼 PstIsite媛 議댁옱븯湲 븣臾몄뿉 ER stress瑜 諛쏆븘꽌 23 nt媛 遺꾨━맂 긽깭쓽 RT-PCR 궛臾쇱 젣븳슚냼 PstI쓣 泥섎━븯뿬룄 젅떒릺吏 븡뒗떎. 洹몃윭굹 ER stress瑜 諛쏆 븡 XBP1 mRNA뿉뒗 PstI site瑜 媛吏怨 엳湲 븣臾몄뿉, 씠寃껋쓽 RT-PCR 궛臾쇱뿉 젣븳슚냼 PstI쓣 泥섎━븯硫 以묎컙씠 젅떒맂떎. 利 ER stress瑜 諛쏆쑝硫 450 bp (-23 nt)媛 굹굹吏留 ER stress瑜 諛쏆 븡쑝硫 473 bp (+23 nt) 473 bp 떒렪쓽 以묒븰뿉 PstI쑝濡 젅떒맂 2媛쒖쓽 떒렪(290 bp, 183 bp)씠 굹궃떎. 씠泥섎읆 젣븳슚냼 PstI 泥섎━뿉 뵲씪꽌 媛곴컖 떎瑜 湲몄씠濡 젅떒릺뒗 듅꽦쓣 씠슜븯뿬 hypothermia媛 꽭룷뿉 뼱뒓 젙룄쓽 ER stress濡 옉슜븯뒗吏瑜 援щ퀎븷 닔 엳떎.

Fig. 1.

Schematic representation of XBP1 mRNA splicing detection by RT-PCR. RT-PCR analysis of total RNA was performed to simultaneously detect both spliced and unspliced XBP1 mRNA, which is 473 bp without ER stress, but when ER stress is applied, 450 bp, which is 23 bp away, is detected. The removed 23 bp contains the restriction enzyme Pst1. When PCR product was digested with restriction enzyme Pst1, mRNA under ER stress condition was 473 bp, but mRNA without ER stress was cleaved, resulting in 183 bp and 290 bp on the 2% agarose gel, respectively.


PC12 꽭룷뒗 collagen-coated flask뿉꽌 85% RPMI 1640 諛곗(25 mM HEPES buffer, 10% heat inactivated horse serum, 5% heat-inactivated fetal bovine serum, 2 mM L-glutamine, 1 mM sodium pyruvate, 1 g/l D-(+)-glucose, 25 μg/ml streptomycin, 25 U/ml penicillin쓣 룷븿)궗슜븯뿬 37°C/5% CO2 議곌굔뿉꽌 諛곗뼇븯떎. 꽭룷쓽 hypothermia 泥섎━ 삩룄뒗 32°C떎. RNA zol-B Kit (TEL-TEST, Inc. TX, USA)瑜 궗슜 total RNA瑜 遺꾨━븯떎. 異⑹떎룄 80%쓽 PC12 꽭룷瑜 뿬윭 議곌굔쓽 hypothermia 泥섎━븳 썑 4°C phosphate-buffered saline(PBS)濡 2쉶 꽭泥 썑 RNA zol-B 1 ml뿉 homogenization 븯떎. Chloroform 200 μl쓣 泥④븯뿬 옒 꽎뼱二쇨퀬 12,000 rpm (4°C)뿉꽌 15遺꾧컙 썝떖 遺꾨━븯뿬 뼸 500 μl쓽 긽痢듭븸뿉 500 μl쓽 isopropanol瑜 泥④븯뿬 12,000 rpm (4°C)뿉꽌 10遺꾧컙 썝떖 遺꾨━븯뿬 移⑥쟾臾쇱쓣 뼸뿀떎. 移⑥쟾臾쇱쓣 75% ethanol (4°C) 0.1 ml濡 꽭泥 썑 怨듦린以묒뿉 嫄댁“븯뿬 DW뿉 끃씤 썑 NanoDrop Lite UV-spectrophotometer (Thermo Scientific, Waltham, MA, USA)濡 젙웾븯떎. 꽭룷뿉꽌 異붿텧븳 mRNA쓽 poly A뿉 oligo d(T) primer瑜 寃고빀떆耳 뿭쟾궗 슚냼瑜 씠슜빐 cDNA瑜 빀꽦븯떎. 二쇳삎 cDNA뿉 븳 DNA primer, dNTP, 궡뿴꽦 DNA polymerase瑜 븿쑀븯뒗 諛섏쓳븸 以묒뿉 紐⑹쟻쑝濡 븯뒗 double strand DNA瑜 뿴 蹂꽦븯떎(94°C, 30 sec). 뿴 蹂꽦뿉 쓽빐 깮湲 single strand DNA뿉 primer瑜 annealing 븯떎(55°C, 30 sec). DNA polymerase뿉 쓽븳 긽蹂댁꽦 DNA瑜 빀꽦븯떎. 뿴 蹂꽦遺꽣 긽蹂댁꽦 DNA 빀꽦源뚯 25~30 cycle쓣 諛섎났븯뒗뜲, 紐⑹쟻 DNA 떒렪뿉 뵲씪 理쒕 슚쑉쓣 뼸쓣 닔 엳뒗 議곌굔씠 떖씪꽌 쟻떦븯寃 꽕젙 議곌굔쓣 議곗젅븷 븘슂媛 엳떎. PCR쓽 template濡 궗슜븯湲 쐞빐 M-MLV (Promega)瑜 씠슜븯뿬 cDNA瑜 빀꽦븯떎. 遺꾨━븳 3 μg쓽 RNA瑜 oligo d(T), nuclease-free water 븿猿 1.5 ml tube뿉 꽔怨 70°C뿉꽌 5遺꾧컙 媛뿴븯뿬 denature 떆궓 떎쓬 뼹쓬뿉꽌 李④쾶 떇엺 썑, M-MLV 5X reaction buffer 6 μl, dNTP mixture (2.5 mM) 4 μl, M-MLV RT 200 units, 옱議고빀 RNasin® Ribonuclease Inhibitor 25 unit瑜 泥④븯怨 nuclease-free water濡 理쒖쥌 諛섏쓳웾쓣 30 μl濡 留욎텣 떎쓬 42°C뿉꽌 90遺꾧컙 諛섏쓳떆耳곕떎. 諛섏쓳 썑뿉뒗 95°C뿉꽌 2遺꾧컙 M-MLV RT瑜 inactivation 떆궓 썑 Nuclease-Free Water 70 μl쓣 뜑븯뿬 理쒖쥌쟻쑝濡 100 μl濡 留욎텣 떎쓬 PCR뿉 2 μl뵫 궗슜븯떎. PCR 諛섏쓳븸 50 μl뿉 F-primer (5’-AAACAGAGTAGCAGCTCAGACTGC-3’) R-primer (5’-TCCTTCTGGGTAGACCTCTGGGAG-3’)瑜 94°C~30珥, 68°C~30珥, 72°C~1遺꾩쑝濡 30쉶 諛섎났븯떎. PCR 理쒖쥌 궛臾 8 μl쓣 PstI 젣븳슚냼濡 37°C뿉꽌 2떆媛 룞븞 泥섎━븳 떎쓬뿉 2% agarose gel뿉꽌 쟾湲곗쁺룞븯뿬 UV긽뿉꽌 諛대뱶瑜 愿李고븯떎.

PC12 꽭룷瑜 32°C뿉꽌 媛곴컖 젙빐吏 떆媛 룞븞 삩 泥섎━븯떎(Fig. 2A). 젙긽쟻 꽭룷 諛곗뼇 삩룄(37°C)뿉꽌 諛곗뼇븳 議곌뎔쓽 꽭룷뿉 鍮꾧탳븯뿬 1, 3, 7떆媛 삩 泥섎━맂 꽭룷媛 ER stress瑜 뜙 諛쏅뒗 寃쏀뼢쓣 蹂댁떎. 씠뒗 삩뿉꽌 꽭룷쓽 쟾泥댁쟻씤 궗媛 뼥뼱吏뒗 뼥뼱吏뒗 寃껉낵 愿怨꾧 엳뒗 寃 媛숇떎. 洹몃윭굹 삩 泥섎━瑜 3씪 룞븞 븷 寃쎌슦뿉뒗 삤엳젮 꽭룷媛 ER stress瑜 젙긽꽭룷쓽 2諛 젙룄 諛쏆븯떎(Fig. 2B). 寃곌뎅 꽭룷뿉 誘몄튂뒗 삩쓽 쁺뼢, 떒湲곌컙뿉뒗 궗 긽깭濡 ER stress媛 씪떆쟻쑝濡 빟빐吏吏留 湲 떆媛꾩뿉꽌뒗 ER stress濡 옉슜븯떎. 1씪 룞븞 삩 泥섎━뿉꽌뒗 ER stress瑜 嫄곗쓽 諛쏆 븡븯쑝굹, 1씪 삩 泥섎━ 떎쓬뿉 1떆媛꾩뿉꽌 3떆媛 젙룄 37°C 泥섎━瑜 븯硫 議곌뎔蹂대떎 빟 2諛 媛源뚯씠 ER stress瑜 諛쏆쑝硫 5떆媛 泥섎━뿉꽌뒗 議곌뎔 닔以쑝濡 궡젮솕떎(Fig. 2C). 2씪媛 삩 泥섎━ 썑 Fig. 1怨 媛숈씠 37°C 泥섎━瑜 1, 3, 5떆媛 泥섎━븳 寃곌낵쓽 삎깭뒗 Fig. 1C 쑀궗븯떎(Fig. 2D). 씠 寃곌낵뒗 鍮꾨줉 1~2씪쓽 삩 泥섎━ 썑뿉 1~3떆媛 젙룄쓽 37°C 泥섎━뿉 쓽빐꽌 ER stress瑜 留롮씠 諛쏅뒗 긽깭媛 릺吏留 5떆媛 젙룄뿉꽌뒗 議곌뎔 닔以쑝濡 룎븘삤뒗 寃껋쓣 븣 닔 엳떎. Fig. 2D뿉꽌 媛숈씠 2떆媛 삩 泥섎━ 썑 37°C 泥섎━븯硫 ER stress瑜 諛쏅뒗떎. 씠 긽깭뿉꽌 떎떆 32°C 泥섎━븳 寃곌낵 ER stress媛 誘몃명븯吏留 긽듅븯뒗 諛섎㈃ 떎떆 37°C 泥섎━뿉 쓽빐꽌 ER stress瑜 뜙 諛쏆븯떎(Fig. 2E). 씠 寃곌낵뒗 32°C 37°C 泥섎━瑜 諛섎났븿쑝濡쒖꽌 ER stress瑜 以꾩씪 닔 엳떎, 留뚯빟뿉 삩 泥섎━踰뺤쓣 移섎즺濡 궗슜븷 寃쎌슦뿉 씪젙븳 媛꾧꺽쑝濡 37°C 泥섎━瑜 븿쑝濡쒖꽌 썝븯吏 븡뒗 ER stress瑜 以꾩씪 닔 엳뒗 媛뒫꽦쓣 蹂댁씤떎. 삩 泥섎━꽭룷뿉꽌 LiCl 泥섎━ 愿怨꾩뾾씠 GSK-3β pS9媛 利앷릺뒗 뿰援 寃곌낵媛 蹂닿퀬릺뼱 엳떎(Bretteville et al., 2012). 씠뒗 Fig. 2B쓽 寃곌낵 媛숈씠 삩 泥섎━뿉 쓽빐꽌 ER stress瑜 諛쏅뒗 寃껋쓣 쓽誘명븳떎. 洹몃━怨 LiCl뿉 쓽븳 GSK-3 빐媛 삩 泥섎━맂 꽭룷뿉꽌 泥댁삩 쑀諛 tau怨 씤궛솕瑜 媛먯냼瑜 넻빐꽌 ER stress瑜 쁽븯寃 媛먯냼떆궎뒗 寃껋쑝濡 異붿젙븷 닔 엳떎(Rzechorzek et al., 2015). 洹몃윭굹 蹂 떎뿕 寃곌낵뒗 LiCl 泥섎━꽭룷뿉꽌 삩 泥섎━ 愿怨꾩뾾씠 ER stress媛 媛먯냼릺뿀떎(Fig. 2F). 삩 泥섎━뿉 쓽븳 GSK-3 빐 tau쓽 諛쒗쁽怨 씤궛솕瑜 넻븳 ER stress瑜 議곗젅湲곗쟾쓣 遺꾨챸븯寃 븷 븘슂媛 엳떎. 洹 寃곌낵뒗 ER stress瑜 理쒖냼솕븳 泥댁삩踰 궗슜뿉 洹쇰낯쟻씤 臾몄젣빐寃곗뿉 떎留덈━瑜 젣怨듯븷 寃껋씠떎.

Fig. 2.

The effects of hypothermia treatment for the ER stress detected by XBP1 mRNA splicing. (A) PC12 cells were exposed to hypothermia (32°C) for different time durations (1, 3 & 7 h). (B) PC12 cells were exposed to hypothermia for different time durations (1 day & 3 days). (C) & (D) PC12 cells under control after hypothermia treatment for different time durations. (E) PC12 cells were exposed to hypothermia for repeated processing of intervals. (F) PC12 cells were exposed to hypothermia conditions with 20 mM lithium chloride, respectively. The control treatment temperature for all experiments is 37°C. Total RNA was isolated from indicated cells after treatment hypothermia, and the expression levels of the indicated genes were determined by RT-PCR and Pst1 digestion, the resulting undigested Pst1 fragments were normalized against GAPDH expression. DNA bands were quantified using the ImageJ program (NIH, Bethesda, MD, USA). The experiment was carried out three times and the results are statistically processed.


ACKNOWLEDGEMENTS

씠 뿰援щ뒗 異⑸궓븰援 븰닠뿰援щ퉬뿉 쓽빐 吏썝릺뿀쓬.

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