第二十章癌基因和抑癌基因演示文稿

第二十章癌基因和抑癌基因演示文稿當(dāng)前1頁，總共86頁。（優(yōu)選）第二十章癌基因和抑癌基因當(dāng)前2頁，總共86頁。Measuringtransformationin-vitroNormaltransformed

腫瘤是機(jī)體在各種致瘤因素的作用下，局部組織的細(xì)胞在基因水平上失掉了對其生長的正常調(diào)控，導(dǎo)致異常增生而形成的新生物。

致瘤因素

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基因改變

→腫瘤細(xì)胞當(dāng)前3頁，總共86頁。DevelopmentofCancerDefectivecellcyclescheckpointsmechanismsallowserrorsinthecellduplicationprocesstopersistintothenextgenerationandcanleadtoandregulatedproliferationandthedevelopmentofcancer.Twodifferenttypesofmutationscontributetocancerformation:activatingmutationsinproto-oncogeneandinactivatingmutationsintumorsuppressorgenes.當(dāng)前4頁，總共86頁。OncogenesStimulateProliferationInhibitDifferentiationInhibitApoptosisTumorSuppressorGenesInhibitProliferationPromoteDifferentiationStimulateApoptosis當(dāng)前5頁，總共86頁。一、癌基因的基本概念癌基因（oncogene）是指存在于正常細(xì)胞內(nèi)，與細(xì)胞生長發(fā)育調(diào)控有關(guān)的一組結(jié)構(gòu)基因。癌基因發(fā)生結(jié)構(gòu)異?；虮磉_(dá)異常時(shí)，可以引起細(xì)胞癌變。癌基因可按其來源不同而分為病毒癌基因（v-onc）和細(xì)胞癌基因（c-onc）。

當(dāng)前6頁，總共86頁。Oncogeneswerefirstdiscoveredincertainretrovirusesandwerelateridentifiedascancer-causingagentsinmanyanimalsFirstlinkbetweenvirusesandcancerproposedbyFrancisPeytonRousin1910(NobelPrize,1966):cell-freeextractsfromchickentumorsinjectedintohealthychickenscausednewtumors.HistoryofoncogeneRous

Peyton：The1966NobelPrizeinPhysiologyorMedicine當(dāng)前7頁，總共86頁。雞肉瘤病毒基因組結(jié)構(gòu)圖

調(diào)節(jié)和啟動(dòng)轉(zhuǎn)錄

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長末端重復(fù)序列癌基因正常的病毒基因產(chǎn)生病毒核心蛋白產(chǎn)生逆轉(zhuǎn)錄酶和整合酶

產(chǎn)生病毒外膜蛋白產(chǎn)生酪氨酸蛋白激酶當(dāng)前8頁，總共86頁。RousSarcomaVirus(RSV)DiscoveredbyHaroldVarmusandBishop,1975-76(NobelPrize,1989).Atransformingretrovirus:acancer-causingsingle-strandedRNAvirusthatusesreversetranscriptaseenzymetomakessDNA,thendsDNA,whichintegratesintohostDNA.Note:notalloncogenescausedbyviruses.100’sofoncogenesnowknown.HumanT-cellleukemiavirus(HTLV)isahumanRV;codesaTF.當(dāng)前9頁，總共86頁。RetrovirallifecycleFigure6RetrovirallifecycleRetroviruseshavetwoidenticalcopiesofaplussingle-strandedRNAgenomeandanouterenvelopecontainingprotrudingviralglycoproteins.Afterenvelopeglycoproteinsonavirioninteractwithaspecifichost-cellmembraneproteinorgroupofproteins,theretroviralenvelopefusesdirectlywiththeplasmamembranewithoutfirstundergoingendocytosis(step1).Followingfusion,thenucleocapsidentersthecytoplasmofthecell;thendeoxynucleosidetriphosphatesfromthecytosolenterthenucleocapsid,whereviralreversetranscriptaseandotherproteinscopythessRNAgenomeofthevirusintoadsDNAcopy(step2).TheviralDNAcopyistransportedintothenucleus(onlyonehost-cellchromosomeisdepicted)andintegratedintooneofmanypossiblesitesinthehost-cellchromosomalDNA(step3).TheintegratedviralDNA,referredtoasaprovirus,istranscribedbythehost-cellRNApolymerase,generatingmRNAs(lightred)andgenomicRNAmolecules(darkred).Thehost-cellmachinerytranslatestheviralmRNAsintoglycoproteinsandnucleocapsidproteins(step4).ThelatterassemblewithgenomicRNAtoformprogenynucleocapsids,whichinteractwiththemembrane-boundviralglycoproteins,.Eventuallythehost-cellmembranebudsoutandprogenyvirionsarepinchedoff(step5).當(dāng)前10頁，總共86頁。OriginofTransformingRetroviruses病毒癌基因v-src來源于宿主細(xì)胞的C-SRC基因當(dāng)前11頁，總共86頁。逆轉(zhuǎn)錄復(fù)制整合轉(zhuǎn)錄感染病毒RNARNA-DNA前病毒DNA細(xì)胞基因組DNA病毒RNA-癌基因RNA病毒顆粒宿主細(xì)胞再感染宿主細(xì)胞攜帶癌基因的病毒顆粒RNA病毒與宿主細(xì)胞基因組整合過程示意圖Proto-oncogenes癌變當(dāng)前12頁，總共86頁。因此，病毒癌基因（v-onc）就是指一類存在于腫瘤病毒中，能使宿主細(xì)胞發(fā)生惡性轉(zhuǎn)化的基因。當(dāng)前13頁，總共86頁。病毒癌基因的特點(diǎn)

病毒癌基因無內(nèi)含子,而原癌基因通常有內(nèi)含子或插入序列。病毒癌基因較原癌基因有較強(qiáng)的轉(zhuǎn)化細(xì)胞功能，病毒癌基因與同源的原癌基因在外顯子序列中存在著微小的差別。病毒癌基因常會(huì)出現(xiàn)堿基取代或堿基缺失等突變,而原癌基因則較少發(fā)現(xiàn)這類突變。病毒癌基因通常丟失了原癌基因兩端的某些調(diào)控序列，而在病毒高效啟動(dòng)子作用下有較高的轉(zhuǎn)錄活性。當(dāng)前14頁，總共86頁。二、細(xì)胞癌基因細(xì)胞癌基因(c-onc)又稱為原癌基因（proto-oncogene），存在于細(xì)胞基因組中、正常情況下處于靜止或低水平（限制性）表達(dá)狀態(tài)，對維持細(xì)胞正常功能具有重要作用，當(dāng)受到致癌因素作用被活化而導(dǎo)致細(xì)胞惡變的基因。當(dāng)前15頁，總共86頁。細(xì)胞癌基因的特點(diǎn)：廣泛存在于生物界基因序列高度保守表達(dá)產(chǎn)物對細(xì)胞正常生長、繁殖、發(fā)育和分化起著精確的調(diào)控作用?；蚪Y(jié)構(gòu)發(fā)生異?；虮磉_(dá)失控，導(dǎo)致細(xì)胞生長增殖和分化異常當(dāng)前16頁，總共86頁。二、癌基因活化的4種機(jī)制示意圖當(dāng)前17頁，總共86頁。指來源于病毒等的啟動(dòng)子或增強(qiáng)子插入到細(xì)胞癌基因的附近或內(nèi)部而使其開放并異常轉(zhuǎn)錄。如雞白細(xì)胞增生病毒引起的淋巴瘤，就是由于病毒的DNA序列整合到宿主細(xì)胞c-myc基因附近，成為該基因的強(qiáng)啟動(dòng)子，導(dǎo)致c-myc基因過強(qiáng)表達(dá)。（一）插入激活當(dāng)前18頁，總共86頁。c-myc原癌基因的插入激活當(dāng)前19頁，總共86頁。即基因數(shù)量或拷貝數(shù)目明顯增加。常見的為myc原癌基因，由于其基因數(shù)目的增多而使其表達(dá)的蛋白產(chǎn)物增多。（二）基因擴(kuò)增當(dāng)前20頁，總共86頁。常見的為ras原癌基因的點(diǎn)突變。

ras原癌基因點(diǎn)突變后導(dǎo)致其GTPase活性下降，不能將其結(jié)合的GTP迅速水解，從而使其持續(xù)保持激活狀態(tài)。

正常細(xì)胞H-ras基因堿基序列ATGACGGAATATAAGCTGGTGGTGGTGGGCGCCGGCGGTGTG腫瘤細(xì)胞H-ras基因堿基序列ATGACGGAATATAAGCTGGTGGTGGTGGGCGCCGTCGGTGTG正常細(xì)胞P21蛋白氨基酸序列MetThrGluTyrLysLeuValValValGlyAlaGlyAlaVal腫瘤細(xì)胞P21蛋白氨基酸序列MetThrGluTyrLysLeuValValValGlyAlaValAlaValH-ras基因的點(diǎn)突變

（三）點(diǎn)突變當(dāng)前21頁，總共86頁。RasProto-oncogeneMutatedin30%ofallcancers.A“molecularswitch”inthesignaltransductionpathwayleadingfromgrowthfactorstogeneexpressioncontrollingcellproliferation:GFreceptorRasTFtargetgenesgrowth.AsingleaminoacidchangeinRasproteincancauseconstantstimulationofthepathway,evenintheabsenceofgrowthfactors.當(dāng)前22頁，總共86頁。由于染色體重排而導(dǎo)致細(xì)胞癌基因從正常位置轉(zhuǎn)移到另一位置，常常是插入一啟動(dòng)子后而使其轉(zhuǎn)錄活性增加。Burkitt淋巴瘤中，含有c-myc的8號染色體易位，與14號染色體連接，靠近免疫球蛋白肽鏈的基因，與該區(qū)活性很高的啟動(dòng)子連接而受到活化。c-abl原癌基因，經(jīng)重排后插入到另一稱為bcr基因的啟動(dòng)子之后，而使其轉(zhuǎn)錄活性增加，從而引起慢性粒細(xì)胞性白血病的發(fā)生。

（四）染色體易位當(dāng)前23頁，總共86頁。ChromosomalTranslocationthatcreatesPhiladelphiaChromosomeBCR-ABLOncogene:BreaksinABLGeneofChromosome9andBCRGeneofChromosome22FusionProteincausesChronicMyelogenousLeukemia當(dāng)前24頁，總共86頁。出現(xiàn)新的表達(dá)產(chǎn)物出現(xiàn)過量的正常表達(dá)產(chǎn)物出現(xiàn)異常、截短的表達(dá)產(chǎn)物癌基因激活的結(jié)果：不同癌基因有不同的激活方式，一種癌基因也可有幾種激活方式：c-myc、ras腫瘤細(xì)胞中常發(fā)現(xiàn)兩種或多種細(xì)胞癌基因的活化，如白血病細(xì)胞株HL-60中有c-myc和N-ras的同時(shí)活化?！涸囵B(yǎng)大鼠胚胎成纖維細(xì)胞當(dāng)前25頁，總共86頁。作用于細(xì)胞膜上的受體系統(tǒng)或直接被傳遞至細(xì)胞內(nèi)，通過蛋白激酶活化轉(zhuǎn)錄因子，引發(fā)一系列基因的轉(zhuǎn)錄激活。三、原癌基因的產(chǎn)物與功能sis表達(dá)蛋白P28和PDGF一樣能促進(jìn)血管的生長。（一）細(xì)胞外生長因子例如：當(dāng)前26頁，總共86頁。（二）跨膜的生長因子受體：接受細(xì)胞外的生長信號并將其傳入胞內(nèi)。受體的胞質(zhì)結(jié)構(gòu)區(qū)具有特異的蛋白激酶活性，通過磷酸化作用使其結(jié)構(gòu)發(fā)生改變，增加激酶對底物的活性，促進(jìn)生長信號在胞內(nèi)的傳遞。例如

EGFR、HER2有酪氨酸特異的蛋白激酶活性。當(dāng)前27頁，總共86頁。非受體酪氨酸激酶(src，abl)、絲氨酸/蘇氨酸激酶(raf)，ras蛋白(H-ras，K-ras和N-ras)及磷脂酶(crk產(chǎn)物)。（三）細(xì)胞內(nèi)信號傳導(dǎo)分子原癌基因的產(chǎn)物作為胞內(nèi)信息傳遞體系成員，或者通過影響第二信使作用，將接受到的信號由胞內(nèi)傳至核內(nèi)，促進(jìn)細(xì)胞生長。例如：當(dāng)前28頁，總共86頁。（四）核內(nèi)轉(zhuǎn)錄因子某些癌基因表達(dá)蛋白定位于細(xì)胞核內(nèi)，與靶基因的順式調(diào)控元件相結(jié)合直接調(diào)節(jié)靶基因的轉(zhuǎn)錄活性。例如：c-fos是一種即刻早期反應(yīng)基因(immediateearlygene，IEG)。作為傳遞信息的第三信使。當(dāng)前29頁，總共86頁。①生長因子②生長因子受體③蛋白激酶及其他信號轉(zhuǎn)導(dǎo)組分④細(xì)胞周期蛋白⑤細(xì)胞凋亡調(diào)控因子⑥轉(zhuǎn)錄因子當(dāng)前30頁，總共86頁。原癌基因BRAF所編碼的蛋白質(zhì)屬于絲/蘇氨酸激酶，是MAPK信號通路的重要組成分子，在調(diào)控細(xì)胞增殖、分化等方面發(fā)揮重要作用。四、癌基因表達(dá)產(chǎn)物促進(jìn)腫瘤發(fā)生發(fā)展約60%的黑素瘤中BRAF發(fā)生突變，其第600位氨基酸從纈氨酸突變?yōu)楣劝彼幔╒600E）最為常見，導(dǎo)致B-Raf的持續(xù)激活。（一）BRAF例如：分子靶向藥物威羅菲尼Vemurafenib當(dāng)前31頁，總共86頁。HER2是表皮生長因子受體家族成員，具有蛋白酪氨酸激酶活性，能激活下游信號通路，從而促進(jìn)細(xì)胞增殖和抑制細(xì)胞凋亡。在30%的乳腺癌中HER2基因發(fā)生擴(kuò)增或者過度表達(dá)，其表達(dá)水平與治療后復(fù)發(fā)率和不良預(yù)后顯著相關(guān)。（二）HER2例如：單克隆抗體藥物赫塞汀Herceptin當(dāng)前32頁，總共86頁。慢性粒細(xì)胞白血病患者的9號染色體與22號染色體之間發(fā)生易位，從而融合產(chǎn)生了癌基因BCR-ABL，編碼的蛋白質(zhì)Bcr-Abl具有持續(xù)活化的蛋白酪氨酸激酶活性，能促進(jìn)細(xì)胞增殖，并增加基因組的不穩(wěn)定性。在95%的慢性粒細(xì)胞白血病患者中都伴隨有BCR-ABL融合基因的產(chǎn)生，在一些急性淋巴白血病患者中也有發(fā)現(xiàn)。（三）BCR-ABL例如：分子靶向藥物伊馬替尼Imatinib當(dāng)前33頁，總共86頁。AcquiredmutationsofoncogenesMostcancercausingmutationsinvolvingoncogenesareacquired,notinherited.Theygenerallyactivateoncogenesbychromosomerearrangements,geneduplication,ormutation.Forexample,achromosomerearrangementleadstoformationofthegenecalledBCR-ABL.Thisleadstothediseasechronicmyeloidleukemia(CML).thegain-of-functionmutationsthatconvertproto-oncogenestooncogenesactdominantly;thatis,mutationinonlyoneofthetwoallelesissufficientforinductionofcancer.當(dāng)前34頁，總共86頁。InheritedmutationsofoncogenesAfewcancersyndromesarecausedbyinheritedmutationsofproto-oncogenesMultipleendocrineneoplasiatype2(多發(fā)性內(nèi)分泌瘤)iscausedbyaninheritedmutationinthegenecalledRET.InheritedmutationsinthegenecalledKITcausehereditarygastrointestinalstromaltumors(胃腸道間質(zhì)瘤,GIST).InheritedmutationsinthegenecalledMETcausehereditarypapillaryrenalcancer（乳頭狀腎癌）.當(dāng)前35頁，總共86頁。CancersUsuallyResultfromaSeriesofMutationsinaSingleCellColonCancer:MSH2和MLH1基因失活染色體：改變：基因：5q突變或缺失FAP、APC、MCC？12q突變K-ras18q缺失DCC17q缺失和突變p53正常腸上皮高增殖腸上皮早期腺瘤中期腺瘤晚期腺瘤腺癌轉(zhuǎn)移癌nm23突變DNA低甲基化其他基因的改變（如TGF-βⅡ受體）當(dāng)前36頁，總共86頁。TumorSuppressorGenes?TumorSuppressorgenes:aregenesthatacttoinhibitcellproliferationandtumordevelopment.

IfTumorSuppressorGeneisMutatedInactivatedItwillleadtocelltransformation當(dāng)前37頁，總共86頁。腫瘤抑制基因(tumorsuppressorgene)

腫瘤抑制基因的概念也稱抗癌基因（anticancergene）或抑癌基因，是調(diào)節(jié)細(xì)胞正常生長和增殖的基因。當(dāng)這些基因不能表達(dá)，或者當(dāng)它們的產(chǎn)物失去活性時(shí)，細(xì)胞就會(huì)異常生長和增殖，最終導(dǎo)致細(xì)胞癌變。反之，若導(dǎo)入或激活它則可抑制細(xì)胞的惡性表型。當(dāng)前38頁，總共86頁。DiscoveryofTumorSuppressorsFirstdiscoveredin1960sbyHenryHarris.?Harrisfusedtumorcellswithnormalcellsanddiscoveredsomeofthehybridcellswerenormal.?Harrishypothesizedthatthenormalcellscontainedgeneproductsthatsuppresseduncontrolledcellproliferation.當(dāng)前39頁，總共86頁。Fivebroadclassesofproteinsencodedbytumor-suppressorgenesIntracellularproteins,suchasthep16cyclin-kinaseinhibitor,thatregulateorinhibitprogressionthroughaspecificstageofthecellcycle.Receptorsforsecretedhormones(e.g.,tumorderivedgrowthfactorβ)thatfunctiontoinhibitcellproliferation.Checkpoint-controlproteinsthatarrestthecellcycleifDNAisdamagedorchromosomesareabnormal.Proteinsthatpromoteapoptosis.EnzymesthatparticipateinDNArepair.當(dāng)前40頁，總共86頁。Familialcancer-RbSporadicretinoblastoma–60%ofretinoblastomacases.–Developsinchildrenwithnofamilyhistory.–Occursinoneeye.Hereditaryretinoblastoma–40%ofretinoblastomacases.–Onsettypicallyisearlierthansporadiccases.–Multipletumorsinvolvingbotheyes.Retinoblastoma(Rb)causedbymutatedRbgeneTheFirstTumor-SuppressorGene視網(wǎng)膜母細(xì)胞瘤當(dāng)前41頁，總共86頁。AlfredKnudson’s2-hitmodelTwomutationsarerequiredforthedevelopmentofretinoblastoma.?Sporadicretinoblastoma–Childstartswithtwowildtypealleles(RB+/RB+).–Bothallelesmustmutatetoproducethedisease(RB/RB).–Probabilityofbothmutationsoccurringinthesamecellislow;onlyonetumorforms(e.g.,oneeye).?Hereditaryretinoblastoma–Childstartswithheterozygousalleles(RB/RB+).–Onlyonemutationisrequiredtoproducedisease(RB/RB).–Mutationsresultinginlossofheterozygosity(LOH)aremoreprobableinrapidlydividingcells,andmultipletumorsoccur(e.g.,botheyes).當(dāng)前42頁，總共86頁。Lossofheterozygosity(LOH)雜合性缺失當(dāng)前43頁，總共86頁。Rb基因的表達(dá)產(chǎn)物為P105Rb，在細(xì)胞內(nèi)存在低磷酸化型（活性型）和高磷酸化型（非活性型）兩種類型。不同類型的P105Rb對轉(zhuǎn)錄因子E2F有不同的親和力。Rb基因的作用機(jī)制當(dāng)前44頁，總共86頁。G0G1期Rb蛋白E-2FS期E-2FDNAmRNADNAPRb蛋白當(dāng)前45頁，總共86頁。當(dāng)前46頁，總共86頁。TumorSuppressorsareRecessiveTumorsuppressorsmustbeinactivated?Thismeansbothcopiesmustbelost/mutated當(dāng)前47頁，總共86頁。TumorsuppressorsandfamilialcancerHereditarycanceriscausedbytheinheritanceofonecopyofadefectivetumorsuppressor當(dāng)前48頁，總共86頁。1.Antagonizetheactionofoncogenes–eg.p53isactivatedbyoncogenes.p53protectsagainstcancerbyinducingcellcyclearrestand/orapoptosisFunctionsofTumorSuppressorgenesmyccellgrowthp53當(dāng)前49頁，總共86頁。2.Blockproliferation:–Cellcycleinhibitors:eg.Rb–blocksentryintoSphasebybindingtoandinhibitingRB.INK-4gene:thatproducesP16thatinhibitscdk4/cyclinDaction(tophosphorylateRbgenetoinactivateit’saction)–Repressortranscriptionfactors:e.g.;WT1isarepressorthatappearstosuppresstranscriptionfactor(Insulinlikegrowthfactor)whichwillcontributeinthedevelopmentoftumor.–Activatortranscriptionfactors:e.g.;SMADfamilythatareactivatedbyTGF-β,leadingtoinhibitionofcellproliferation.P53:thatproducesP21thathasthesameactionofP16ininhibitingtheactionofcdk/cyclin.FunctionsofTumorSuppressorgenes當(dāng)前50頁，總共86頁。PTEN通過阻斷PI3K/AKT信號通路抑制細(xì)胞的生長當(dāng)前51頁，總共86頁。3.Induceapoptosis:–Formofcellsuicide.Acellwhichhaslostgrowthcontrolwilloftenundergoapoptosis.–Celldamageor‘stress’canalsoleadtoapoptosis.–p53isacriticalregulatorofapoptosis.Transcriptionfactorwhichactivatespro-apoptoticmoleculesFunctionsofTumorSuppressorgenes當(dāng)前52頁，總共86頁。?Mostcommonlymutatedgeneincancers(50%oftotal).?Whenp53ismutated,DNA-damagedcellsarenotarrestedinG1andDNArepairdoesnottakeplace.?ThisfailuretoarrestDNA-damagedcellswillberepeatedinsubsequentcellcyclespermittingothermutationstoaccumulate,culminatinginneoplastictransformation...tumorformationandcancer.p53Mutations當(dāng)前53頁，總共86頁。p53的結(jié)構(gòu)及其在清除DNA損傷細(xì)胞中的作用

當(dāng)前54頁，總共86頁。p53–theguardianofthegenome當(dāng)前55頁，總共86頁。Regulationofthecellcycle當(dāng)前56頁，總共86頁。4.DNARepair–DNArepairpreventstheaccumulationofmutations–DefectsinDNArepairgenesleadstogenomicinstability–Acceleratestheactivationofoncogenesandthelossoftumorsuppressors–ManycancerpronesyndromesassociatedwithdefectsinDNArepair,BRCA1,ATM,MRE11,NBS,FunctionsofTumorSuppressorgenes當(dāng)前57頁，總共86頁。?Asmallproportionofbreastcancerisheritable.Twogenesareassociatedwithpredispositiontobreastcancer.–BRCA1onchromosome17–BRCA2onchromosome13?NormalfunctionofbothisinrepairofdsDNAbreaks.BreastCancerTumorSuppressors當(dāng)前58頁，總共86頁。Tumorsuppressorgenes-summaryTumorsuppressorgenes–inhibitoncogenes–suppressproliferation–Inducecelldeath–repairDNA–preventmutation?Theseare“l(fā)ossoffunction”orrecessivemutations.?Responsibleforhereditaryformsofcancer?Beingheterozygousenhancestheprobabilityofcancerbutthiswillrequireamutationinthecorrespondingotherallele.e.g.,itneedtobehomozygousforthegene.當(dāng)前59頁，總共86頁。Tumorsuppressorgenes-summaryp53Atranscriptionfactorthatregulatesgenescontrollingcelldivisionandcelldeath.ImportantinthecellularresponsetoDNAdamage.Aidsindecisionbetweenrepairandinductionofcelldeath.RbFunctionsbyalteringtranscriptionfactoractivity.Contributestothecontrolofcellulardivisionbyactingasaninhibitor.APCTheAPCproteinbindsandstimulatesthedegradationofatranscriptionfactor.AbsenceoffunctionalAPCproteinleadstoincreasedcelldivision.BRCABRCAproteinshavemultiplefunctionsincludingrepairingDNAdamageandregulationofgeneexpression.Non-functionalBRCAleadstocompromisedDNArepairandgeneregulation.當(dāng)前60頁，總共86頁。促進(jìn)正常細(xì)胞向腫瘤細(xì)胞轉(zhuǎn)化的因素

當(dāng)前61頁，總共86頁。生長因子

Growthfactors

第三節(jié)當(dāng)前62頁，總共86頁。生長因子(growthfactor)一類由細(xì)胞分泌的、類似于激素的信號分子，多數(shù)為肽類（含蛋白類）物質(zhì)，具有調(diào)節(jié)細(xì)胞生長與分化的作用。當(dāng)前63頁，總共86頁。內(nèi)分泌

(endocrine)旁分泌

(paracrine)自分泌

(autocrine)作用模式：

生長因子分泌后，通過血液運(yùn)輸作用于遠(yuǎn)端靶細(xì)胞細(xì)胞分泌生長因子作用于鄰近其它類型細(xì)胞，對自身細(xì)胞不發(fā)生作用生長因子作用于合成及分泌該生長因子的細(xì)胞本身當(dāng)前64頁，總共86頁。一、生長因子的分類和功能（一）生長因子的分類生長因子名稱組織來源功能表皮生長因子（EGF）唾液腺、巨噬細(xì)胞、血小板等促進(jìn)表皮與上皮細(xì)胞的生長，尤其是消化道上皮細(xì)胞的增殖肝細(xì)胞生長因子（HGF）間質(zhì)細(xì)胞促進(jìn)細(xì)胞分化和細(xì)胞遷移促紅細(xì)胞生成素（EPO）腎調(diào)節(jié)成紅細(xì)胞的發(fā)育類胰島素生長因子（IGF）血清促進(jìn)硫酸鹽參入到軟骨組織促進(jìn)軟骨細(xì)胞的分裂、對多種組織細(xì)胞起胰島素樣作用神經(jīng)生長因子（NGF）頜下腺含量高營養(yǎng)交感和某些感覺神經(jīng)元、防止神經(jīng)元退化血小板源生長因子（PDGF）血小板、平滑肌細(xì)胞促進(jìn)間質(zhì)及膠質(zhì)細(xì)胞的生長、促進(jìn)血管生成轉(zhuǎn)化生長因子α（TGF-）腫瘤細(xì)胞、巨噬細(xì)胞、神經(jīng)細(xì)胞作用類似于EGF，促進(jìn)細(xì)胞惡性轉(zhuǎn)化轉(zhuǎn)化生長因子β（TGF-β）腎、血小板對某些細(xì)胞起促進(jìn)和抑制雙向作用血管內(nèi)皮生長因子（VEGF）低氧應(yīng)激細(xì)胞促進(jìn)血管內(nèi)皮增殖和新生血管分化當(dāng)前65頁，總共86頁。（二）生長因子的功能生長因子的生物學(xué)效應(yīng)主要表現(xiàn)在促進(jìn)細(xì)胞生長、分化、促進(jìn)個(gè)體發(fā)育等方面。但是有些生長因子具有雙重調(diào)節(jié)作用或負(fù)調(diào)節(jié)作用。同一生長因子對不同細(xì)胞的作用有所不同一種細(xì)胞也可受不同生長因子調(diào)節(jié)具有負(fù)調(diào)節(jié)作用的生長因子比較少，人們通常把這種負(fù)調(diào)節(jié)因子（negativegrowthfactor）稱為細(xì)胞生長抑制因子。當(dāng)前66頁，總共86頁。產(chǎn)生相應(yīng)第二信使胞內(nèi)相關(guān)蛋白質(zhì)被磷酸化與膜受體結(jié)合酪氨酸激酶活化蛋白激酶活化核內(nèi)轉(zhuǎn)錄因子活化基因轉(zhuǎn)錄與胞內(nèi)受體結(jié)合生長因子-受體復(fù)合物，活化相關(guān)基因二、生長因子作用機(jī)制當(dāng)前67頁，總共86頁。Theseventypesofproteinsthat

participateincontrollingcellgrowth

growthfactors(I)

growth

factorreceptors(II)

signal-transductionproteins(III)

transcriptionfactors(IV)

pro-oranti-apoptoticproteins(V)

cell

cyclecontrolproteins(VI)

DNA

repairproteins(VII)

ClassVIImutationsgreatlyincreasetheprobabilityofmutationsintheotherclasses.Virus-encodedproteinsthatactivategrowth-factorreceptors(Ia)

alsocaninducecancer.

oncogenestumorsuppressors當(dāng)前68頁，總共86頁。腫瘤的發(fā)生除了與癌基因的異?；罨约澳[瘤抑制基因的異常失活密切相關(guān)外，其與生長因子及其受體的高度活化亦緊密相關(guān)，如EGF、VEGF、TNF及IGF、PDGF等的過度表