人類內生性反轉錄病毒基因的調控與其致病的潛力之研究

為了解LTR上的基因片段對HERV-I轉錄表達的調控，我們以PCR方法從CC-7T的基因分離純化RTVL-Ia上5端LTR全長共497bp，並用pCAT-E和pCAT-P質體建構一系列含CCAAT element ... 資料載入處理中... 跳到主要內容 臺灣博碩士論文加值系統 ::: 網站導覽| 首頁| 關於本站| 聯絡我們| 國圖首頁| 常見問題| 操作說明 English |FB專頁 |Mobile 免費會員 登入| 註冊 功能切換導覽列 (165.22.106.144)您好！臺灣時間：2022/09/0501:25 字體大小：       ::: 詳目顯示 recordfocus 第1筆/ 共1筆  /1頁 論文基本資料 摘要 外文摘要 目次 參考文獻 電子全文 紙本論文 QRCode 本論文永久網址: 複製永久網址Twitter研究生:張念慈研究生(外文):Nien-TzuChang論文名稱:人類內生性反轉錄病毒基因的調控與其致病的潛力之研究論文名稱(外文):StudyontheTranscriptionalRegulationofHumanEndogenousRetrovirusesandtheirPathogenicPotentials指導教授:楊文光、吳成文指導教授(外文):WenK.Yang、Cheng-WenWu學位類別:博士校院名稱:國防醫學院系所名稱:生命科學研究所學門:生命科學學門學類:生物學類論文種類:學術論文論文出版年:2008畢業學年度:96語文別:英文論文頁數:135中文關鍵詞:人類內因性反轉錄病毒、基因轉錄調控、p53突變外文關鍵詞:Humanendogenousretroviruses、Transcriptionalregulation、epigeneticchange、mutantp53相關次數: 被引用:0點閱:442評分:下載:20書目收藏:0 內因性反轉錄病毒(ERVs)廣泛存在於脊椎類動物的基因中，呈現多重複製體並能跟隨著其他基因一起遺傳。

人類內因性反轉錄病毒(HERVs)約佔人類總基因的百分之八，具有LTR-gag-pol-env-LTR結構，其中的LTRs擁有啟動子(promoter)與增強子(enhancer)功能，可進行RNA轉錄、病毒基因插入和polyadenylation。

因此，HERVs的轉錄活化後所產生的病毒RNA、病毒蛋白及反轉錄後的插入突變機制，可能改變周遭基因的轉錄表達，進而導致人類基因病變或癌症。

原則上，絕大部份的人類內因性反轉錄病毒基因有瑕疵而不轉錄，其中的HERV-I經我們以北方吸漬法實驗發現在人類子宮頸癌細胞CC-7T表現得非常微弱而難以測得。

為了解LTR上的基因片段對HERV-I轉錄表達的調控，我們以PCR方法從CC-7T的基因分離純化RTVL-Ia上5'端LTR全長共497bp，並用pCAT-E和pCAT-P質體建構一系列含CCAATelement，ATAAAAAelement或AGTAAAelement片段刪除與定點突變的LTR突變株，接著再以氯黴素乙醯轉移酶(CAT)技術分析LTR突變株於各種不同組織細胞株的基因表現情形。

結果顯示，全長的5'-LTR具有雙向的增強子功能及正向的啟動子功能，其中ATAAAAAelement很像TATAbox具有啟動子功能，CCAATelement則具有部份的增強子功能。

綜合來看，即使CCAAT和ATAAAAA具正向調節HERV-I轉錄活性功能，類似polyadenylationsite的AGTAAAelement則能負向調節HERV-I的轉錄活性，所以造成全長的LTR表現的轉錄活性相當低，幾乎與空載體的背景值相當。

P53為一最常見且最重要的抑癌蛋白，已知它可以調控某些體內的細胞基因，並可以調控外來的許多病毒基因。

我們在研究中發現P53也可以調控HERV-ILTR的轉錄活性，原生型p53可經由與TATA結合蛋白或CAAT結合蛋白作用來抑制HERV-ILTR的轉錄活性，而p53的突變株mtp53(V143A)相反的可以刺激HERV-ILTR的轉錄活性。

因此我們推論，p53的突變可能活化基因中的LTR，並可能因此干擾到細胞中的基因轉錄表達而衍生癌病。

為了進一步分析p53對體內染色體上HERV基因的影響，我們分別檢測原生型p53和p53定點突變株在人類骨癌細胞株Saos-2中對HERV-E、HERV-H、HERV-I、HERV-K和HERV-W基因轉錄的調控。

我們將不同的p53基因轉殖入人類骨癌細胞株Saos-2後，以定量PCR分析HERV的RNA在不同細胞株表達發現HERV基因的轉錄不受原生型p53的抑制，而獨被p53定點突變株中mtp53D281G所誘導表現。

DNAdemethylation和histoneacetylation雖然已知可增加細胞中某些基因的轉錄表達和活化病毒基因，但我們發現在p53基因轉殖的Saos-2細胞株中，5-azacytidine和trichostatinA不能增加HERV基因的轉錄表達。

令人意外的是5-azacytidine和trichostatinA卻獨可在mtp53(D281G)轉殖的Saos-2細胞中誘導增加HERV-E、HERV-H、HERV-I、HERV-K和HERV-W基因的轉錄表達。

綜合以上結果，我們認為原來在人類基因中被管制不表達的HERV基因可能會被細胞中突變的p53蛋白活化，並可能受表觀遺傳變化(epigeneticchange)的增強作用而進一步造成人類基因病變或癌症。

Endogenousretroviruseshaveawidedistributionwithinvertebrates;theyarepresentinmultiplecopiesdispersedthroughoutthegenomesofhostspecies.Humanendogenousretroviruses(HERVs)constituteabout8%ofthehumangenome.TheprevalenceandmaintenanceofHERVselementssuggestthattheymayplayaroleinthebiologyofthehostspecies.HERVsarerelatedtoretroviruseswiththeircharacteristicLTR-gag-pol-env-LTRstructure,inwhichLTRspossesstheenhancerandthepromoterfunctionsforRNAtranscription,viralintegrationandpolyadenylation.TranscriptionalactivationofHERVsissupposedtobepotentiallypathogenicforproducingretroviralproteinsandRNAcopiestoformvirusparticles,proceedingtoretro-transpositionandinsertionmutagenesis,alteringtheexpressionofneighboringordistantcellulargenesfromtheinsertionsitesandeventuallyleadingtoneoplastictransformationorgeneticdisease.Inmostcases,HERVsareeitherstructurallydefectiveorinactiveduepossiblytostringentnegativecontrolmechanisms.SinceRNAtranscriptsofHERV-IinvarioushumancancercellswerehardlydetectablebyNorthernblotsinourpreliminarystudies,weisolatedtheLTRofRTVL-Iaandconstructedsite-specificmutationsforanalysisofthepromoterandenhancerfunctionsbyusingchloramphenicolacetyltransferase(CAT)reporterassay.Ourresultsshowedthat5’-LTRofHERV-Ipossessbi-directionalpromoteractivityandunidirectionalenhanceractivity.TheATAAAAAelement,aTATA-likebox,in5’-LTRmainlyexertsapromoterfunctionwhiletheCCAATelementexhibitsapartialenhancerfunction,andthesetwoelementsintheLTRapparentlyprovidemaximumtranscriptionalactivity.Therefore,thepoortranscriptionalactivityofHERV-ILTRmaybeduetotheAGTAAAsegmentatthepresumedpolyadenylationsitewhichplaysanegativeregulatoryroleincontrollinggeneexpression.P53isatumorsuppressorprotein,anditsmutationsarethemostfrequentlyreportedgeneticalterationsinhumancancers.P53hasbeenshowntorepressoractivatethetranscriptionactivityofseveralcellularandviralpromoters,althoughitseffectonHERVsisnotknown.Wehavefoundthatwildtype(wt)p53canefficientlyrepressthetranscriptionalactivityofHERV-ILTRpresumablythroughtheinteractionofwtp53withtheTATA-bindingproteinsorCAAT-bindingproteins.Inaddition,mutantp53(V143A)canmoreorlessstimulatethetranscriptionalactivityofHERV-ILTR.Theseresultsimplythat,followingp53mutation,LTRsarelikelytobeactivatedandmightaberrantlyregulatetheirneighboringcellulargenesduringthetumorprogressionprocesses.Tostudythepossibleinvolvementofp53inchromosomalHERVexpression,wefurtherexaminedtheRNAtranscriptsofHERV-E,HERV-H,HERV-I,HERV-KandHERV-Wmulti-genefamiliesinp53-nullSaos-2cellstransfectedwithwtp53or“hot-spot”site-specificp53mutants.Quantitativereal-timePCRanalysisshowedthatlimitedRNAexpressionoftheseHERVsinSaos-2cellswerenotaffectedbywtp53butcouldbeelevatedbymtp53(D281G),throughtransientorstabletransfection.5-AzacytidineandtrichostatinA,knowntoactivateendogenousretrovirusesinotheranimals,didnotinduceHERVexpressionintheparentalSaos-2cellsorwtp53transfectantsbutcouldadditivelyincreaseHERVgenesexpressionespeciallyincellsstablytransfectedwithmtp53(D281G).OurresultssuggestthatthestringentcontrolledchromosomalHERVgenesmaybecompromisedbyp53mutation,especiallyatcodon281,incombinationwithepigeneticchromatinalterations,leadingtotheactivationofpotentiallypathogenicretrotransposablegenefunctions. TABLEOFCONTENTSITABLECONTENTSVFIGURECONTENTSVIIATTACHMENTCONTENTSXI中文摘要XIIIABSTRACTXVII1.INTRODUCTION11.1WHATISHUMANENDOGENOUSRETROVIRUSES(HERVS)11.2HERVCLASSIFICATIONANDDISTRIBUTION21.3HERVSTRUCTUREANDCODINGPOTENTIAL51.4CELLULARFUNCTIONSOFHERVSANDITSRELATIONTOHUMANDISEASES71.5THEREGULATIONMECHANISMOFHERVS91.5.1DNAmethylation121.5.2Histonemodificationandchromatinremodeling131.5.3P53151.6SPECIFICAIMSOFSTUDY162.MATERIALSANDMETHODS192.1CELLS192.2DRUGTREATMENT192.3REPORTERPLASMIDSCONSTRUCTION202.4P53MUTANTSCONSTRUCTION212.5DNATRANSFECTION222.6GENERATIONOFSAOS-2CELLLINESWITHP53ORITSMUTANTS222.7CATASSAYS232.8GENOMICDNAISOLATION242.9SOUTHERNBLOT252.10RNAPREPARATION262.11NORTHERNBLOT262.12QUANTITATIVEREAL-TIMERT-PCRANALYSISOFHERVRNALEVEL272.13INHIBITIONOFP53EXPRESSIONWITHSIRNA282.14PACKAGINGCELLS292.15WESTERNBLOT302.16COMETASSAY303.RESULTS333.1HERV-ILTRHASUNI-DIRECTIONALPROMOTERACTIVITYANDBI-DIRECTIONALENHANCERACTIVITY333.2ANALYSESTHEPROMOTERANDENHANCERACTIVITYOFDELETIONMUTANTSOFHERV-ILTR383.4AGTAAAELEMENTPLAYSANEGATIVEREGULATORYROLEINTHEHERV-ILTRPROMOTERANDENHANCERACTIVITY433.5THETRANSCRIPTIONALACTIVITYOFHERV-ILTRISTISSUE-SPECIFIC463.6HYPOMETHYLATIONOFLTRUPON5-AZACTREATMENTINCREASESTHETRANSCRIPTIONALACTIVITYOFTRANSIENTTRANSFECTEDHERV-ILTRBUTNOTTHEGENEEXPRESSIONOFCHROMOSOMALHERV-IGENE483.75-AZACAND/ORTSATREATMENTINDUCEDHERV-IGENEEXPRESSIONONLYINEMBRYONALCELLSBUTNOTSOMATICCELLS573.8BOTHTHEPROMOTERANDENHANCERACTIVITIESOFHERV-ILTRARELOWINHPV-POSITIVECERVICALCARCINOMACELLSBUTHIGHINHPV-NEGATIVECERVICALCARCINOMACELLS593.9TRANSIENTEXPRESSIONOFWILDTYPEP53REPRESSESWHILEMUTANTP53STIMULATESTHETRANSCRIPTIONALACTIVITYOFHERV-ILTR.633.10WTP53REPRESSIONOFTHEHERV-ILTRTRANSCRIPTIONALACTIVITYMAYBEMEDIATEDTHROUGHTHETATA-ANDCAAT-LIKEELEMENTS.663.11TRANSIENTLYEXPRESSEDMTP53SINCREASETHEGENEEXPRESSIONOFHERV-E,HERV-H,HERV-I,HERV-KANDHERV-WINSAOS-2CELLS723.12STABLEEXPRESSEDMTP53SINCREASETHEEXPRESSIONOFVARIOUSHERVGENEFAMILIESASWELLASTHEHERV-INEIGHBORINGHAPTOGLOBINGENESINSAOS-2CELLS763.13THETRANSCRIPTIONALACTIVITYOFHERV-IMAYREGULATEITSNEIGHBORINGHP&HPRGENESEXPRESSIONINSAOS-2CELLS823.14BOTH5-AZACANDTSATREATMENTADDITIVELYINDUCEDHERVSGENEEXPRESSIONINSAOS-2CLONEWITHMUTANTP53(D281G)EXPRESSION833.15RNAINTERFERENCETOSTUDYTHEEFFECTOFP53ONHERVSGENEREGULATION863.16INDUCTIONEXPRESSIONOFHERVSINMETASTASISCELLSOFMDA-MB-231ANDCL1-5913.17INDUCTIONOFHERVEXPRESSIONINTHEPACKAGINGCELLSOFNTERA-2933.18EFFECTOFWTP53ORMTP53SONDNADAMAGE954.DISCUSSION1015.CONCLUSION1136.REFERENCES115 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