【复旦大学-癌生物学学习】_肿瘤与翻译后修饰-Neddylation-CRL通路调控肿瘤发生与靶向治疗.ppt

肿瘤与翻译后修饰Neddylation CRL通路调控肿瘤发生与靶向治疗 蛋白翻译后修饰精密调控蛋白稳态 2 磷酸化泛素化甲基化乙酰化糖基化SumolationNeddylation 3 Ub 泛素 Ubiquitin 一种高度保守的 由76个氨基酸组成的多肽 E1 泛素激活酶 Ubiquitin activatingenzyme 人类仅有1 2种 E2 泛素结合酶 Ubiquitin conjugatingenzyme 人类约有40种 E3 泛素 蛋白连接酶 Ubiquitin proteinligase 人类有600多种 泛素 蛋白酶体系统 UPS 泛素 蛋白酶体系统 UPS 作为抗肿瘤靶点 4 Ub 泛素 Ubiquitin E1 泛素活化酶 人类仅有1 2种 E2 泛素结合酶 人类约有40种 E3 泛素连接酶 人类约有600多种 Bortezomib 硼替佐米 5 E3决定底物特异性 主要分为2类 RINGReallyinterestingnewgeneHECTHomologoustoE6APC terminus CRL泛素连接酶调控肿瘤发生 Adams etal NatRevCancer2004FrescasD etal NatRevCancer2008 6 CRL CRL Cullin RingLigase CRL 最大的多亚基泛素连接酶家族 调控20 经UPS降解的蛋白 CRL泛素连接酶活化调控与靶向治疗 7 鉴定CRL核心组成亚基作为新型抗肿瘤分子靶点 研究内容一 8 针对CRL家族抗肿瘤分子靶点发现策略 9 ROC1 针对CRL的抗肿瘤分子靶点 10 揭示了CRL经neddylation过度修饰而在肿瘤内持续激活的新机制 研究内容二 11 Neddylation新型蛋白翻译后修饰通路 12 14 15 Neddylation活化 普遍的促癌机制与抗癌靶点 肠癌 NatureCommunication 2014 张令强教授组肝细胞癌 Oncotarget 2015 Mart nez Chantar教授组 靶向neddylation通路在原位肿瘤的抗肿瘤效果 0371012 d 16 探索靶向neddylation CRL通路抗肿瘤治疗的作用机制 研究内容三 17 Neddylation CRL通路靶向治疗作用机制 识别蛋白 ROC1 抑癌蛋白底物积聚 肿瘤 18 InductionofsenescenceandautophagybyknockdownofROC1E3ubiquitinligasetosuppressthegrowthoflivercancercells RBX1 ROC1Ubiquitinligase JiaLJetal CellDivision 2009 RBX1 ROC1 CRL ROC1overexpressioninhepatocellularcarcinomas HCC ROC1overexpressionpredictedapoorprognosisinHCCpatients ROC1silencingsuppressedthegrowthoflivercancercells ROC1silencingsuppressedthegrowthoflivercancers ROC1silencinginducedG2 Marrestandcellsenescence ROC1silencing inducedcellsenescenceisp21 dependent ROC1silencinginducedautophagyasanovelcellularresponseinlivercancercells ROC1knockdowninducesautophagyinlivercancercells ROC1silencinginducedautophagyviaDeptor mTORaxis ROC1silencinginducedtheaccumulationofDeptortotriggerautophagyresponse ROC1knockdowninducesautophagyandsenescencesequentially IndependentinductionofautophagyandsenescencebyROC1knockdown AutophagyinducedbyROC1knockdownisasurvivalsignal BlockageofautophagypathwaytriggersapoptosisinROC1 silencedcells BlockageofautophagypathwaypromotedROC1knockdown inducedcancercelldeathbytriggeringapoptosis BlockageofautophagypathwaypromotedROC1knockdown inducedcancercelldeathbytriggeringapoptosis Overactivatedneddylationpathwayasatherapeutictargetinlungcancer Neddylation修饰与肿瘤 42 假说 Neddylation修饰通路在肿瘤内可能发生过度活化 并因而持续激活CRL泛素连接酶 Isneddylationpathwayoveractivatedinlungcancer OverexpressionofNAE1 E1 andUBC12 E2 inlungcancer ExpressionofNAE1 UBA3 E1 andUBC12 E2 inlungcancer NegativeassociationofexpressionofNAE1orUBC12andoverallsurvivaloflungcancerpatients Overactivationofglobalproteinneddylationinlungcancer Cullin1neddylationiselevatedinlungcancer Theentireneddylationpathwayisoveractivatedinhumanlungcancer Howisneddylationpathwayoveractivatedinlungcancer Transcriptionalactivationstatusofneddylationcomponents Theactivationofneddylationpathwayinlungcancercells Thetranscriptionalactivationmayrepresentamolecularmechanismresponsiblefortheoveractivationoftheneddylationpathway Doestheoveractivatedneddylationpathwayserveasatherapeutictarget MLN4924specificallyinhibitedneddylationpathway MLN4924inhibitedcellproliferationandcolonyformation MLN4924inhibitedtranswellcellmigrationandmotility EfficacyofneddylationinhibitiononexperimentallungmetastasisI LLC GFP RFPexperimentalmetastaticmodels EfficacyofneddylationinhibitiononexperimentallungmetastasisII A549 GFPexperimentalmetastaticmodels MLN4924inhibitedthemalignantphenotypesoflungcancer WhatisthemechanismofactionofMLN4924inlungcancer MLN4924blockedcullinneddylationandinactivatedCRL MLN4924inducedapoptosisorsenescenceinacellline dependentmanner EffectsofMLN4924ontheexpressionofapoptosis regulatoryproteins RoleofNOXAincell fatedetermination apoptosisvssenescence uponneddylationinhibition JNatlCancerInst JNCI 2014 系统揭示neddylation通路在肿瘤内过度活化状态 阐明CRL泛素连接酶在肿瘤内持续激活的新机制 鉴定neddylationE2和E3酶作为新的抗肿瘤靶点 建议根据Neddylation活化水平遴选患者精准治疗 65 该发现的科学意义与转化前景 致谢 Prof YiSunUniversityofMichiganProf PingWangTongJiUniversityProf RobertM HoffmanUniversityofCaliforniaProf LakShinJeongSeoulNationalUniversityProf JieLiuFudanUniversityProf MingsongWangShanghaiJiaoTongUniversity 国家自然科学基金委中国科技部 上海市科委 上海市卫计委 。