Quantitative Proteomics Reveals Cellular Targets of Celastrol 英文参考文献.docVIP

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Quantitative Proteomics Reveals Cellular Targets of Celastrol 英文参考文献.doc

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Quantitative Proteomics Reveals Cellular Targets of Celastrol 英文参考文献

QuantitativeProteomicsRevealsCellularTargetsof Celastrol JakobHansen1,2*¤,JohanPalmfeldt1,S?renVang1,3,ThomasJ.Corydon4,NielsGregersen1,PeterBross1 1ResearchUnitforMolecularMedicine,AarhusUniversityHospital,Skejby,Aarhus,Denmark,2DepartmentofForensicMedicine,AarhusUniversity,Aarhus,Denmark, 3DepartmentofMolecularMedicine,AarhusUniversityHospital,Skejby,Aarhus,Denmark,4DepartmentofHumanGenetics,AarhusUniversity,Aarhus,Denmark Abstract Celastrol, a natural substance isolated from plant extracts used in traditional Chinese medicine, has been extensively investigatedasapossibledrugfortreatmentofcancer,autoimmunediseases,andproteinmisfoldingdisorders.Although studies focusing on celastrol’s effects in specific cellular pathways have revealed a considerable number of targets in a diversearrayofinvitromodelsthereisanessentialneedforinvestigationsthatcanprovideaglobalviewofitseffects.To assess cellular effects of celastrol and to identify target proteins as biomarkers for monitoring treatment regimes, we performed large-scale quantitative proteomics in cultured human lymphoblastoid cells, a cell type that can be readily preparedfromhumanbloodsamples.Celastrolsubstantiallymodifiedtheproteomecompositionand158ofthecloseto 1800proteinswithrobustquantitationshowedatleasta1.5foldchangeinproteinlevels.Up-regulatedproteinsplaykey roles in cytoprotection with a prominent group involved in quality control and processing of proteins traversing the endoplasmicreticulum.Increasedlevelsofproteinsessentialforthecellularprotectionagainstoxidativestressincluding hemeoxygenase1,severalperoxiredoxinsandthioredoxinsaswellasproteinsinvolvedinthecontrolofironhomeostasis werealsoobserved.Specificanalysisofthemitochondrialproteomestronglyindicatedthatthemitochondrialassociationof certainantioxidantdefenseandapoptosis-regulatingproteinsincreasedincellsexposedtocelastrol.Analysisofselected mRNA transcripts showed that celastrol activated several different stress response pathways and dose response