chapter 14 癌基因与抑癌基因

Liyan

XuOncogeneCancersuppressivegeneThebasicconcept1oncogene:

Thesegenescodeforproteinsthatarecapableofstimulatingcellgrowthanddivision.Innormaltissuesandorganisms,suchgrowth-stimulatingproteinsareregulated,sothatgrowthisappropriatelylimited.However,changes/mutationinthesegenesmayresultinlossofgrowthregulation,leadingtouncontrolledcellproliferationandtumordevelopment.Thesechangedgenesareknownasoncogenes,becausetheyinducetheoncogenicstate—cancer.Oncogenesaredominant,becauseachange/mutationofonlyoneofthecell’stwocopiesofthatgenecanleadtotumorformation.Thebasicconcept2proto-oncogenes:Tto-oncogenesisalsocalledascellularoncogenes.3virusoncogene:thesegenesareinviruses,mayleadingtouncontrolledcellproliferationandtumordevelopment.Virusoncogenesarehomologwiththatcorrespondingcellularoncogenes.Thebasicconcept4cancersuppressivegenes:Thesegenescodeforproteinswhosenormalfunctionistoturnoffcellgrowth.Achange/mutationinoneofthesegrowth-limitinggenesmayresultinaproteinproductthathaslostitsgrowthlimitingability.Thenormalformsofsuchgensehavebeenshowntosuppresstumorgrowthandareknownastumorsuppressorgenesoranti-oncogenesaswell.Becausebothcellularcopiesofatumorsuppressorgenemustbemutatedtofoilitsgrowth-limitingaction,thesegenesarerecessiveinnature.Fig.20-1StructureofRSVgenome9392bpLTRLTRgagpolenvsrctyrosinekinase526residue60kDwidetypeviralgenesoncogenetoinitiateandregulatetranscriptionThepp60V-SRCisanchoredtotheplasmamembraneviaanN-terminalmyristylgroupFig.20-2IntegrationofRNAvirusgenomeandhostcellgenomeRNAvirus+++provirusDNAvirusRNAhostcellc-onc.v-onc.Mtooncogeneamplificationinthegenome.pointmutationtoobtainastrongpromoterorenhancer.avianleukemiavirusgenomehostcellgenomessRNAdsDNAc-mycLTRtoincreasec-mycgeneexpression,30-100times,comparewithnoinfection.Mtooncogeneamplificationinthegenome.pointmutationBurkitlymphoma14chromosomeIgHgeneregulationregion8chromosomec-myctoincreasec-mycgeneexpressionobviouslyt（8:14）Mtooncogeneamplificationinthegenome.pointmutationrasorc-mycexpressionof

rasorc-myc

isincreasedobviouslyamplification123nMtooncogeneamplificationinthegenome.pointmutationGGCGTCH-rasGlyValDNAProteincarcinomanormalnucleuscytoplasmmembraneextracellularSISPDGFreceptorRAS/Gpro.erbB-2EGFkinasetargetstargetsSRCDNAmRNARNApol.targetskinasecAMPDGPKCERCa2+AAACPGPKAtargetskinaseeffectseffectsPIP2+Fig.20-3Oncogeneandsignaltransductionforgrowth418PLCPLA2IP3nucleuscytoplasmmembraneextracellularSISPDGFreceptorRAS/Gpro.erbB-2EGFkinasetargetstargetsSRCDNAmRNARNApol.targetskinasecAMPDGPKCERCa2+AAACPGPKAtargetskinaseeffectseffectsPIP2+Fig.20-3Oncogeneandtransductionofinformationforgrowth418PLCPLA2IP3Phospho-rylationsitenucleuscytoplasmmembraneextracellularSISPDGFreceptorRAS/Gpro.erbB-2EGFkinasetargetstargetsSRCDNAmRNARNApol.targetskinasecAMPDGPKCERCa2+AAACPGPKAtargetskinaseeffectseffectsPIP2+Fig.20-3Oncogeneandtransductionofinformationforgrowth418PLCPLA2IP3Ca2+nucleuscytoplasmmembraneextracellularSISPDGFreceptorRAS/Gpro.erbB-2EGFkinasetargetstargetsSRCDNAmRNARNApol.targetskinasecAMPDGPKCERCa2+AAACPGPKAtargetskinaseeffectseffectsPIP2+Fig.20-3Oncogeneandtransductionofinformationforgrowth418PLCPLA2IP3tumorsuppressorgenestwoexamplesRb:13q14.1-14.2,27exon,completelength180kb,mRNA4.7kb,encodingprotein105kD,928residues,locateinnucleus,inactiveform:phosphorylation

Rb,activeform:non-phosphorylation

Rb,beabletobindactivatedtranscriptionfactorE-2F,beabletoinhibiteRNApolymeraseIandRNApolymeraseIII.p53:17p13,11exon,completelength16-20kb,mRNA2.8kb,encodingprotein53kD,393residues,locateinnucleus,isphosphorylated,tetramer.cellDNAdamagep53

damagedDNArepaircellapoptosiscellsurviverepairissuccessfulbyp53repairisunsuccessfulbyp53

OncogeneandtumorsuppresorgeneOurexperimentresultabouttheoncogenesandtumorsuppressorgenesforesophageal

cancer

normalembryoesophagealepithelialcellhumanpapillomavirusE6andE7genesplasmidimmortalesophagealcelltransfection12-o-tetradecanoylphorbol-13-acetate,TPAcarcinogenesophagealcancercellcancerationdifferencecDNAclonemRNAdifferenceupdowncDNAarrayupclone:33downclone:28suppressionsubtractivehybridizationupclone:62downclone:56SummaryThebasicconcept:oncogene,

proto-oncogene,virusoncogene,tumorsuppressorgeneMechanismononcogeneactivatedFunctionofoncogeneandtumorsuppressorgene选择题练习癌基因与抑癌基因1.细胞原癌基因A正常人细胞也检测到的癌基因B只在肿瘤细胞中出现C加入化学致癌物到正常细胞后才出现D是细胞经过转化才出现E感染致癌病毒才出现2.关于细胞癌基因,正确的叙述是A存在于RNA病毒中B存在于DNA病毒中C存在于正常细胞基因组中D正常细胞出现可导致肿瘤E只存在于肿瘤细胞细胞3.致癌病毒A使人体直接致癌B使正常细胞转化为癌细胞C均为DNA病毒D均为RNA病毒E含转化酶4.不属于癌基因产物的是A化学致癌物B生长因子类似物C结合GTP的蛋白质D结合DNA的蛋白质E酪氨酸蛋白激酶5.有关抑癌基因,错误的叙述是A能抑制细胞的分化B能抑制细胞过度生长C突变后可导致肿瘤形成D可诱导细胞凋亡E最早发现的抑癌基因是Rb6.有关P53蛋白,错误的描述是A其基因位于17p13,突变后可致癌B能引发修复失败的细胞程序自杀C有“基因卫士”的称号D有转录因子作用E能激活解链酶7.有关Rb基因,错误的描述是A位于13q14B是一种抑癌基因C其作用与E-2F有关D其编码蛋白为P21E突变后可导致肿瘤发生8.关于凋亡,正确的叙述是A是一种病理过程B是细胞坏死C由意外事件引起的细胞损伤造成D由基因控制的细胞自我消亡的过程E与癌基因的表达调控无关9.生殖细胞抑癌基因的突变可引起A生殖功能障碍B各种先天性的肿瘤C家族性的肿瘤易感性D后代的发育正常E家族性癌症发病率下降10.使癌基因活化的因素有A正常基因表达增强B正常基因表达减少C抑癌基因表达增强D细胞增殖、分化加强E点突变11.TheoncogenewhichcanencodeepidermalgrowthfactorreceptorisAsrcBrasCmycDsisEerb-B12.TheoncogenewhichcanencodeGTPbindingproteinisAsrcBrasCmycDsisEerb-B13.TheoncogenewhichcanencodeproteinhavingTPKactivityisAsrcBrasC