12第20章癌基因、抑癌基因與生長(zhǎng)因子課件

第二十章

chapter20癌基因、抑癌基因與生長(zhǎng)因子Oncogenes,Anti-oncogenesandGrowthFactors第二十章

chapter20癌基因、抑癌基因1癌基因、抑癌基因與生長(zhǎng)因子的關(guān)系oncogenesanti-oncogenescellsgrowthfactorsup-regulationdown-regulationproduct癌基因、抑癌基因與生長(zhǎng)因子的關(guān)系oncogenes2癌基因（oncogene）病毒癌基因（virusoncogene,v-onc）細(xì)胞癌基因（cellularoncogene,C-onc）原癌基因（proto-oncogene）癌基因（oncogene）3Oncogenesaregeneswhichcontrolthegrowthanddifferentiationofcells(控制細(xì)胞生長(zhǎng)和分化),theabnormalityoftheirstructureorexpression(結(jié)構(gòu)異?；虮磉_(dá)異常)cancausecancer(引起細(xì)胞癌變).原癌基因(proto-oncogenes，pro-onc)IfOncogenespresentinthenormalcellulargenome,theyarenamedasproto-oncogenesorcellularoncogenes.存在于生物正常細(xì)胞基因組中的癌基因。癌基因(oncogene)Oncogenesaregeneswhichcont4癌基因

Oncogenes第一節(jié)癌基因

Oncogenes第一節(jié)5存在于病毒基因組中的癌基因，它不編碼病毒的結(jié)構(gòu)成分，對(duì)病毒復(fù)制也沒有作用，但可以使細(xì)胞持續(xù)增殖。Virusoncogenes

areoncogenesintheviralgenome，althoughtheydon’tencodethestructuralproteinsofthevirusesanddon’tplayrolesintheviralreplication,buttheycanpromotecellproliferationcontinuously.一、病毒癌基因病毒癌基因(virusoncogene,v-onc)存在于病毒基因組中的癌基因，它不編碼病毒的結(jié)構(gòu)成分，對(duì)病毒復(fù)6*thestructureofviralgenomeregulateandinitiatetranscriptionLTRgagpolenvsrcLTRlongterminalrepeat

thenormalviralgenes

reversetranscriptaseoncogenecertainglycoproteinsoftheviralenvelopeprotein-tyrosinekinase

coreproteinofthevirus*thestructureofviralgenome712第20章癌基因、抑癌基因與生長(zhǎng)因子課件812第20章癌基因、抑癌基因與生長(zhǎng)因子課件9Viraloncogenecomesfromcellularoncogene.Viraloncogenecomesfromcell10廣泛存在于生物界Presentinbiologicalkingdomextensively基因序列高度保守Thesequenceareconservativehighly維持正常生理功能、調(diào)控細(xì)胞生長(zhǎng)和分化起重要作用Playvitalrolesinnormalcontrolofcelllife

被激活后，導(dǎo)致正常細(xì)胞癌變

Causecellstobecomecancerouswhenoncogenesareactivated二、細(xì)胞癌基因(Cellularoncogenes)廣泛存在于生物界二、細(xì)胞癌基因(Cellularonco11ClassificationandproductofthecellularoncogenesSrcfamily：protein-tyrosinekinase

Rasfamily：p21，akindofsmallG-protein

Mycfamily：DNAbindingproteinSisfamily：p28(truncatedPDGF),growthfactorMybfamily：nucleartranscriptionalfactorClassificationandproductof12FunctionalclassesofoncogenesClassificationoftheexpressedproductsOncogenesPropertiesoftheexpressedproductsGrowthfactorssisPDGFβ-chaingrowthfactorInt-2growthfactorReceptorproteinerb-BtruncatedEGFreceptortyrosinekinaseros,neuligandsarenotknownNon-receptorsrc,yesmembraneassociatedtyrosinekinaseproteinkinasesfpstyrosinekinasesnotassociatedwithmembraneraf,mosserine-threonineproteinkinasesGproteinsH-ras,K-ras,N-rasmembraneassociatedsmallGproteinsTranscriptionfactorsmyc,fos,junregulatorsofproliferationerbA,skiregulatorsofdifferentiationCellcycleregulatorsPRAD1cyclinrelatedfactorsFunctionalclassesof13Extracellulargrowthfactors（生長(zhǎng)因子）：sisTrans-membranegrowthfactorsreceptors（生長(zhǎng)因子受體）:c-src、c-abl、c-mos、c-rafIntracellularsignalfactors（細(xì)胞內(nèi)信號(hào)分子）:c-src、c-abl、c-ras、c-mas、ras、crkNucleartranscriptionfactors（核轉(zhuǎn)錄因子）：myc、fos三、原癌基因的產(chǎn)物與功能Extracellulargrowthfactors（生1412第20章癌基因、抑癌基因與生長(zhǎng)因子課件1512第20章癌基因、抑癌基因與生長(zhǎng)因子課件16（1）獲得啟動(dòng)子與增強(qiáng)子

obtainpromoterandenhancer四、癌基因活化的機(jī)制

mechanismofoncogeneactivationSuchasinsertionofpre-viruswhichcantainsstrongerpromoterandenhancerinLTR.（1）獲得啟動(dòng)子與增強(qiáng)子四、癌基因活化的機(jī)制

mecha17（2）染色體易位(Chromosomaltranslocation)duringchromosomaltranslocation,thetranslocationandtherearrangementofcertaingenesoccurred,sothatnoactivityoftheoriginalproto-oncogenemovedtoastrongpromoterorenhancerwasactivatedandexpressed,leadingtotumoroccurred

（2）染色體易位(Chromosomaltransloc18ThechromosomaltranslocationcharacteristicofBurkittlymphomaTranslocationofoncogenesThechromosomaltranslocation1912第20章癌基因、抑癌基因與生長(zhǎng)因子課件20（三）原癌基因擴(kuò)增

Proto-oncogenesamplification原癌基因拷貝數(shù)量的增加.

TherelationshipoftheN-myconcogeneandRbgene（三）原癌基因擴(kuò)增原癌基因拷貝數(shù)量的增加.Th21（四）點(diǎn)突變（Pointmutationincodingregion）ThecomponentsoftheH-ras-1oncogene（四）點(diǎn)突變（Pointmutationincodin22LossofchromosomalmaterialanddeletionofregulatorysequencesInsertionofpre-virusesDemethylationofDNACo-operationbetweenoncogenesLossofchromosomalmateriala23出現(xiàn)新的表達(dá)產(chǎn)物appearsthenewproduct出現(xiàn)過量的正常表達(dá)產(chǎn)物appearstheexcessivenormalproduct出現(xiàn)異常、截短的表達(dá)產(chǎn)物appearstheabnormalortruncatedproduct癌基因激活的結(jié)果：出現(xiàn)新的表達(dá)產(chǎn)物癌基因激活的結(jié)果：24抑癌基因

Anti-oncogenes第二節(jié)抑癌基因

Anti-oncogenes第二節(jié)25抑癌基因(cancersuppressivegene,anti-oncegene)

一、抑癌基因的基本概念Theyaregeneswhichcan

Inhibitthegrowthofnormalcellsandrestraintherateofdivisionofnormalcells.抑制細(xì)胞生長(zhǎng)和增殖的基因。抑癌基因(cancersuppressivegene,26細(xì)胞雜交試驗(yàn)（Cellularhybridizationexperiments）hybridizationnormalcellslosesomegenescancerouscellsnormalcellscancerouscellsnoncanceroushybridcellscancerouscells1cancerouscells2noncanceroushybridcellshybridization細(xì)胞雜交試驗(yàn)（Cellularhybridization27二、常見的抑癌基因二、常見的抑癌基因28（一）視網(wǎng)膜母細(xì)胞瘤基因（Rb基因）G0G1期Rb蛋白E-2FS期E-2FDNAmRNADNA三、抑癌基因的作用機(jī)制PRb蛋白（一）視網(wǎng)膜母細(xì)胞瘤基因（Rb基因）G0G1期Rb蛋白E-29（二）P53P53蛋白解鏈酶復(fù)制因子AP21蛋白細(xì)胞停滯于G1期細(xì)胞調(diào)亡酸性區(qū)核心區(qū)堿性區(qū)P53蛋白DNA損傷P21基因P53蛋白抑制P53蛋白成功修復(fù)修復(fù)失敗（二）P53P53蛋白解鏈酶復(fù)制因子AP21蛋白細(xì)胞停滯于G30生長(zhǎng)因子

Growthfactors

第三節(jié)生長(zhǎng)因子

Growthfactors第三節(jié)31生長(zhǎng)因子(growthfactor)一、概述通過質(zhì)膜上特異的受體，將信息傳遞至細(xì)胞內(nèi)部，調(diào)節(jié)細(xì)胞生長(zhǎng)與增殖的多肽類物質(zhì)。GrowthfactorsTheyarepolypeptidesubstancewhichcantransmitamessagetotheinteriorofthecellsbythespecificreceptorsontheplasmamembrane,inthiswaytheycanregulatethegrowthandproliferationofthecells.生長(zhǎng)因子(growthfactor)一、概述通過質(zhì)膜上特異32YYYbloodvesselSignalingsubstanceYreceptortargetcellstimulationtargetcellsecretivecellY作用模式：

內(nèi)分泌

(endocrine)旁分泌

(paracrine)自分泌

(autocrine)YYYbloodvesselSignalingsubs3312第20章癌基因、抑癌基因與生長(zhǎng)因子課件34Howthegrowthfactorsact?producethesecondarymessagephosphorylatetheassociateproteinsincellbindtothemembranereceptorsactivateprotein-tyrosinekinaseactivatetheproteinkinaseactivatethenucleartranscriptionfactorsgenetranscriptionbindtothenuclearreceptorsgrowthfactor-receptorcomplex,activatetheassociategene.Howthegrowthfactorsact?35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(zhǎng)因子-受體復(fù)合物，活化相關(guān)基因二、生長(zhǎng)因子作用機(jī)制產(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3612第20章癌基因、抑癌基因與生長(zhǎng)因子課件3712第20章癌基因、抑癌基因與生長(zhǎng)因子課件38在某些生理或病理?xiàng)l下，細(xì)胞接受到某種信號(hào)所觸發(fā)的并按一定程序緩慢死亡的過程。誘導(dǎo)因素：野生型p53基因抑制因素：突變型p53基因、神經(jīng)生長(zhǎng)因子(NGF)（一）細(xì)胞凋亡(apoptosis)Therelationshipofoncogenes、anti-oncogenes、growthfactorsanddiseases在某些生理或病理?xiàng)l下，細(xì)胞接受到某種信號(hào)所觸發(fā)的并按一定程39myc、fos的激活促平滑肌細(xì)胞增生；p53低表達(dá)或突變。2.動(dòng)脈粥樣硬化：PDGF過量產(chǎn)生ras、myb、myc、fos等過量表達(dá)，有關(guān)的生長(zhǎng)因子有IGF、TGF、FGF。（二）心血管疾病3.心肌肥厚：1.原發(fā)性高血壓：myc、fos的激活促平滑肌細(xì)胞增生；2.動(dòng)脈粥樣硬化：40腫瘤細(xì)胞特征之一：增殖失控生長(zhǎng)信號(hào)自給自足。生長(zhǎng)抑制信號(hào)失敏。復(fù)制能力失控。腫瘤細(xì)胞特征之一：增殖失控生長(zhǎng)信號(hào)自給自足。41p53基因突變PTEN基因突變Fas信號(hào)減弱，F(xiàn)asL表達(dá)上調(diào)：凋亡淋巴細(xì)胞逃避免疫反應(yīng)。病毒抗凋亡蛋白抑制宿主細(xì)胞凋亡：p35——BcL-2同源HBX——結(jié)合p53E6——促進(jìn)p53分解腫瘤細(xì)胞特征之二：逃避凋亡p53基因突變腫瘤細(xì)胞特征之二：逃避凋亡42腫瘤細(xì)胞特征之三：侵襲和轉(zhuǎn)移包括六個(gè)步驟：原發(fā)腫瘤細(xì)胞穿透組織基底膜；穿破血管或淋巴管壁進(jìn)入血液循環(huán)；停留于靶器官淋巴管和毛細(xì)血管壁內(nèi)皮細(xì)胞上；穿出血管侵入周圍組織；繼續(xù)生長(zhǎng)、增殖；新生血管長(zhǎng)入形成轉(zhuǎn)移瘤；腫瘤擴(kuò)散的分子基礎(chǔ)腫瘤細(xì)胞特征之三：侵襲和轉(zhuǎn)移包括六個(gè)步驟：腫瘤擴(kuò)散的分子基礎(chǔ)4312第20章癌基因、抑癌基因與生長(zhǎng)因子課件4412第20章癌基因、抑癌基因與生長(zhǎng)因子課件45腫瘤血管生成和轉(zhuǎn)移

腫瘤血管生成和轉(zhuǎn)移46第二十章

chapter20癌基因、抑癌基因與生長(zhǎng)因子Oncogenes,Anti-oncogenesandGrowthFactors第二十章

chapter20癌基因、抑癌基因47癌基因、抑癌基因與生長(zhǎng)因子的關(guān)系oncogenesanti-oncogenescellsgrowthfactorsup-regulationdown-regulationproduct癌基因、抑癌基因與生長(zhǎng)因子的關(guān)系oncogenes48癌基因（oncogene）病毒癌基因（virusoncogene,v-onc）細(xì)胞癌基因（cellularoncogene,C-onc）原癌基因（proto-oncogene）癌基因（oncogene）49Oncogenesaregeneswhichcontrolthegrowthanddifferentiationofcells(控制細(xì)胞生長(zhǎng)和分化),theabnormalityoftheirstructureorexpression(結(jié)構(gòu)異常或表達(dá)異常)cancausecancer(引起細(xì)胞癌變).原癌基因(proto-oncogenes，pro-onc)IfOncogenespresentinthenormalcellulargenome,theyarenamedasproto-oncogenesorcellularoncogenes.存在于生物正常細(xì)胞基因組中的癌基因。癌基因(oncogene)Oncogenesaregeneswhichcont50癌基因

Oncogenes第一節(jié)癌基因

Oncogenes第一節(jié)51存在于病毒基因組中的癌基因，它不編碼病毒的結(jié)構(gòu)成分，對(duì)病毒復(fù)制也沒有作用，但可以使細(xì)胞持續(xù)增殖。Virusoncogenes

areoncogenesintheviralgenome，althoughtheydon’tencodethestructuralproteinsofthevirusesanddon’tplayrolesintheviralreplication,buttheycanpromotecellproliferationcontinuously.一、病毒癌基因病毒癌基因(virusoncogene,v-onc)存在于病毒基因組中的癌基因，它不編碼病毒的結(jié)構(gòu)成分，對(duì)病毒復(fù)52*thestructureofviralgenomeregulateandinitiatetranscriptionLTRgagpolenvsrcLTRlongterminalrepeat

thenormalviralgenes

reversetranscriptaseoncogenecertainglycoproteinsoftheviralenvelopeprotein-tyrosinekinase

coreproteinofthevirus*thestructureofviralgenome5312第20章癌基因、抑癌基因與生長(zhǎng)因子課件5412第20章癌基因、抑癌基因與生長(zhǎng)因子課件55Viraloncogenecomesfromcellularoncogene.Viraloncogenecomesfromcell56廣泛存在于生物界Presentinbiologicalkingdomextensively基因序列高度保守Thesequenceareconservativehighly維持正常生理功能、調(diào)控細(xì)胞生長(zhǎng)和分化起重要作用Playvitalrolesinnormalcontrolofcelllife

被激活后，導(dǎo)致正常細(xì)胞癌變

Causecellstobecomecancerouswhenoncogenesareactivated二、細(xì)胞癌基因(Cellularoncogenes)廣泛存在于生物界二、細(xì)胞癌基因(Cellularonco57ClassificationandproductofthecellularoncogenesSrcfamily：protein-tyrosinekinase

Rasfamily：p21，akindofsmallG-protein

Mycfamily：DNAbindingproteinSisfamily：p28(truncatedPDGF),growthfactorMybfamily：nucleartranscriptionalfactorClassificationandproductof58FunctionalclassesofoncogenesClassificationoftheexpressedproductsOncogenesPropertiesoftheexpressedproductsGrowthfactorssisPDGFβ-chaingrowthfactorInt-2growthfactorReceptorproteinerb-BtruncatedEGFreceptortyrosinekinaseros,neuligandsarenotknownNon-receptorsrc,yesmembraneassociatedtyrosinekinaseproteinkinasesfpstyrosinekinasesnotassociatedwithmembraneraf,mosserine-threonineproteinkinasesGproteinsH-ras,K-ras,N-rasmembraneassociatedsmallGproteinsTranscriptionfactorsmyc,fos,junregulatorsofproliferationerbA,skiregulatorsofdifferentiationCellcycleregulatorsPRAD1cyclinrelatedfactorsFunctionalclassesof59Extracellulargrowthfactors（生長(zhǎng)因子）：sisTrans-membranegrowthfactorsreceptors（生長(zhǎng)因子受體）:c-src、c-abl、c-mos、c-rafIntracellularsignalfactors（細(xì)胞內(nèi)信號(hào)分子）:c-src、c-abl、c-ras、c-mas、ras、crkNucleartranscriptionfactors（核轉(zhuǎn)錄因子）：myc、fos三、原癌基因的產(chǎn)物與功能Extracellulargrowthfactors（生6012第20章癌基因、抑癌基因與生長(zhǎng)因子課件6112第20章癌基因、抑癌基因與生長(zhǎng)因子課件62（1）獲得啟動(dòng)子與增強(qiáng)子

obtainpromoterandenhancer四、癌基因活化的機(jī)制

mechanismofoncogeneactivationSuchasinsertionofpre-viruswhichcantainsstrongerpromoterandenhancerinLTR.（1）獲得啟動(dòng)子與增強(qiáng)子四、癌基因活化的機(jī)制

mecha63（2）染色體易位(Chromosomaltranslocation)duringchromosomaltranslocation,thetranslocationandtherearrangementofcertaingenesoccurred,sothatnoactivityoftheoriginalproto-oncogenemovedtoastrongpromoterorenhancerwasactivatedandexpressed,leadingtotumoroccurred

（2）染色體易位(Chromosomaltransloc64ThechromosomaltranslocationcharacteristicofBurkittlymphomaTranslocationofoncogenesThechromosomaltranslocation6512第20章癌基因、抑癌基因與生長(zhǎng)因子課件66（三）原癌基因擴(kuò)增

Proto-oncogenesamplification原癌基因拷貝數(shù)量的增加.

TherelationshipoftheN-myconcogeneandRbgene（三）原癌基因擴(kuò)增原癌基因拷貝數(shù)量的增加.Th67（四）點(diǎn)突變（Pointmutationincodingregion）ThecomponentsoftheH-ras-1oncogene（四）點(diǎn)突變（Pointmutationincodin68LossofchromosomalmaterialanddeletionofregulatorysequencesInsertionofpre-virusesDemethylationofDNACo-operationbetweenoncogenesLossofchromosomalmateriala69出現(xiàn)新的表達(dá)產(chǎn)物appearsthenewproduct出現(xiàn)過量的正常表達(dá)產(chǎn)物appearstheexcessivenormalproduct出現(xiàn)異常、截短的表達(dá)產(chǎn)物appearstheabnormalortruncatedproduct癌基因激活的結(jié)果：出現(xiàn)新的表達(dá)產(chǎn)物癌基因激活的結(jié)果：70抑癌基因

Anti-oncogenes第二節(jié)抑癌基因

Anti-oncogenes第二節(jié)71抑癌基因(cancersuppressivegene,anti-oncegene)

一、抑癌基因的基本概念Theyaregeneswhichcan

Inhibitthegrowthofnormalcellsandrestraintherateofdivisionofnormalcells.抑制細(xì)胞生長(zhǎng)和增殖的基因。抑癌基因(cancersuppressivegene,72細(xì)胞雜交試驗(yàn)（Cellularhybridizationexperiments）hybridizationnormalcellslosesomegenescancerouscellsnormalcellscancerouscellsnoncanceroushybridcellscancerouscells1cancerouscells2noncanceroushybridcellshybridization細(xì)胞雜交試驗(yàn)（Cellularhybridization73二、常見的抑癌基因二、常見的抑癌基因74（一）視網(wǎng)膜母細(xì)胞瘤基因（Rb基因）G0G1期Rb蛋白E-2FS期E-2FDNAmRNADNA三、抑癌基因的作用機(jī)制PRb蛋白（一）視網(wǎng)膜母細(xì)胞瘤基因（Rb基因）G0G1期Rb蛋白E-75（二）P53P53蛋白解鏈酶復(fù)制因子AP21蛋白細(xì)胞停滯于G1期細(xì)胞調(diào)亡酸性區(qū)核心區(qū)堿性區(qū)P53蛋白DNA損傷P21基因P53蛋白抑制P53蛋白成功修復(fù)修復(fù)失?。ǘ㏄53P53蛋白解鏈酶復(fù)制因子AP21蛋白細(xì)胞停滯于G76生長(zhǎng)因子

Growthfactors

第三節(jié)生長(zhǎng)因子

Growthfactors第三節(jié)77生長(zhǎng)因子(growthfactor)一、概述通過質(zhì)膜上特異的受體，將信息傳遞至細(xì)胞內(nèi)部，調(diào)節(jié)細(xì)胞生長(zhǎng)與增殖的多肽類物質(zhì)。GrowthfactorsTheyarepolypeptidesubstancewhichcantransmitamessagetotheinteriorofthecellsbythespecificreceptorsontheplasmamembrane,inthiswaytheycanregulatethegrowthandproliferationofthecells.生長(zhǎng)因子(growthfactor)一、概述通過質(zhì)膜上特異78YYYbloodvesselSignalingsubstanceYreceptortargetcellstimulationtargetcellsecretive