Regulation of PERK Signaling and Leukemic Cell Survival by a Novel Cytosolic Isoform of the UPR Regulator GRP78BiP 英文参考文献.docVIP

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Regulation of PERK Signaling and Leukemic Cell Survival by a Novel Cytosolic Isoform of the UPR Regulator GRP78BiP 英文参考文献.doc

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Regulation of PERK Signaling and Leukemic Cell Survival by a Novel Cytosolic Isoform of the UPR Regulator GRP78BiP 英文参考文献

RegulationofPERKSignalingandLeukemicCellSurvival byaNovelCytosolicIsoformoftheUPRRegulator GRP78/BiP MinNi,HuiZhou,ShiuanWey,PeterBaumeister,AmyS.Lee* DepartmentofBiochemistryandMolecularBiologyandtheUSC/NorrisComprehensiveCancerCenter,UniversityofSouthernCaliforniaKeckSchoolof Medicine,Los Angeles,California,UnitedStatesofAmerica Abstract Theunfoldedproteinresponse(UPR)isanevolutionarilyconservedmechanismtoallowcellstoadapttostresstargeting the endoplasmic reticulum (ER). Induction of ER chaperone GRP78/BiP increases protein folding capacity; as such it representsamajorsurvivalarmofUPR.ConsideringthecentralimportanceoftheUPRinregulatingcellsurvivalanddeath, evidence is emerging that cells evolve feedback regulatory pathways to modulate the key UPR executors, however, the precisemechanismsremaintobeelucidated.Here,wereportthefortuitousdiscoveryofGRP78va,anovelisoformofGRP78 generatedbyalternativesplicing(retentionofintron1)andalternativetranslationinitiation.Bioinformaticandbiochemical analysesrevealedthatexpressionofGRP78vaisenhancedbyERstressandisnotablyelevatedinhumanleukemiccellsand leukemiapatients.IncontrasttothecanonicalGRP78whichisprimarilyanERlumenalprotein,GRP78vaisdevoidoftheER signaling peptide and is cytosolic. Through specific knockdown of endogenous GRP78va by siRNA without affecting canonicalGRP78,weshowedthatGRP78vapromotescellsurvivalunderERstress.WefurtherdemonstratedthatGRP78va hastheabilitytoregulatePERKsignalingandthatGRP78vaisabletointeractwithandantagonizePERKinhibitorP58IPK . OurstudydescribesthediscoveryofGRP78va,anovelcytosolicisoformofGRP78/BiP,andthefirstcharacterizationofthe modulation of UPR signaling via alternative splicing of nuclear pre-mRNA. Our study further reveals a novel survival mechanisminleukemiccellsandothercelltypeswhereGRP78vaisexpressed. Citation:NiM,ZhouH,WeyS,BaumeisterP,LeeAS(2009)RegulationofPERKSignalingandLeukemicCellSurvivalbyaNovelCytosolicIsoformoftheUPR RegulatorGRP78/BiP.PLoSONE4(8):e6868.doi:10.1