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1、关于癌基因抑癌基因与生长因子第1页，讲稿共155张，创作于星期二 细胞的正常生长与增殖由两大类基因调控：细胞的正常生长与增殖由两大类基因调控：正调节信号正调节信号 促进细胞生长和增殖，并阻止其促进细胞生长和增殖，并阻止其发生终末分化。发生终末分化。负调控信号负调控信号 抑制增殖抑制增殖,促进分化、成熟和衰促进分化、成熟和衰老，最后凋亡。老，最后凋亡。这两类基因中任何一种或它们共同的变化，这两类基因中任何一种或它们共同的变化，即有可能引起细胞增殖失控导致肿瘤的发生即有可能引起细胞增殖失控导致肿瘤的发生。第2页，讲稿共155张，创作于星期二癌基因与抑癌基因的作用机制涉及基因表达调癌基因与抑癌基因的
2、作用机制涉及基因表达调控及细胞分裂、分化。控及细胞分裂、分化。癌基因可编码类生长因子多肽及其受体分子，癌基因可编码类生长因子多肽及其受体分子，通过细胞内信息传递系统刺激细胞增殖。通过细胞内信息传递系统刺激细胞增殖。肿瘤的发生与癌基因、抑癌基因和生长因子三肿瘤的发生与癌基因、抑癌基因和生长因子三者的关系密切相关。者的关系密切相关。第3页，讲稿共155张，创作于星期二第一节 癌基因第4页，讲稿共155张，创作于星期二l癌基因（癌基因（oncogeneoncogene）就是具有增加癌源性或转化潜能，）就是具有增加癌源性或转化潜能，导致其编码区或调节区域遗传性状发生改变的基因。导致其编码区或调节区域遗
3、传性状发生改变的基因。l癌基因可分为两大类：一类是致瘤病毒中能在体内诱癌基因可分为两大类：一类是致瘤病毒中能在体内诱发肿瘤并在体外引起细胞转化的基因，即病毒癌基因发肿瘤并在体外引起细胞转化的基因，即病毒癌基因（viral oncogene,v-oncviral oncogene,v-onc）；另一类是存在于细胞基）；另一类是存在于细胞基因组中、正常情况下处于静止或低水平（限制性）表达状因组中、正常情况下处于静止或低水平（限制性）表达状态，对维持细胞正常功能具有重要作用，当受到致癌因素态，对维持细胞正常功能具有重要作用，当受到致癌因素作用被活化而导致细胞恶变的基因，即原癌基因作用被活化而导致细胞
4、恶变的基因，即原癌基因（protooncogeneprotooncogene，pro-oncpro-onc）或称细胞癌基因）或称细胞癌基因（cellular oncogenecellular oncogene，c-oncc-onc）。）。一、病毒癌基因和细胞癌基因 （一）概念第5页，讲稿共155张，创作于星期二 癌癌基基因因名名称称用用3 3个个斜斜体体小小写写字字母母表表示示，如如mycmyc、rasras、srcsrc。l肿瘤病毒是一类能使宿主产生肿瘤或使培养细肿瘤病毒是一类能使宿主产生肿瘤或使培养细胞转化成癌细胞的动物病毒。胞转化成癌细胞的动物病毒。l其核酸组成分为其核酸组成分为DNAD
5、NA病毒病毒和和RNARNA病毒病毒。l病毒癌基因病毒癌基因是一类存在于肿瘤病毒（大多数是一类存在于肿瘤病毒（大多数是逆转录病毒）中的、能使靶细胞发生恶性转是逆转录病毒）中的、能使靶细胞发生恶性转化的基因。化的基因。第6页，讲稿共155张，创作于星期二 l19111911年，年，Reyton Rous Reyton Rous 报道将鸡肉瘤的无细胞滤液报道将鸡肉瘤的无细胞滤液注射给健康鸡后，可诱导发生肉瘤，表明无细胞滤液注射给健康鸡后，可诱导发生肉瘤，表明无细胞滤液含致病原，可传播肿瘤。含致病原，可传播肿瘤。l19321932年，年，ShopeShope发现，野生棉尾兔的皮肤肿瘤也可借助发现，野
6、生棉尾兔的皮肤肿瘤也可借助无细胞滤液传播。无细胞滤液传播。l肿瘤进展：开始，癌细胞处于肿瘤进展：开始，癌细胞处于“休眠休眠”状态，被化学状态，被化学因子、病毒等唤醒后，变的无法无天。因子、病毒等唤醒后，变的无法无天。lRousRous提出病毒致癌理论：即传播肿瘤的无细胞滤液提出病毒致癌理论：即传播肿瘤的无细胞滤液中含的是病毒。中含的是病毒。l这种感染性颗粒后来被证实是逆转录病毒这种感染性颗粒后来被证实是逆转录病毒(RNA(RNA病毒病毒)。RousRous因此获得因此获得19661966年诺贝尔生理和医学奖。年诺贝尔生理和医学奖。癌基因的发现第7页，讲稿共155张，创作于星期二The Nobe
7、l Prize in Physiology or Medicine 1966 Tumor-inducing viruses第8页，讲稿共155张，创作于星期二Peyton RousUSARockefeller UniversityNew York,NY,USAB:1879D:1970第9页，讲稿共155张，创作于星期二鸡肉瘤病毒（鸡肉瘤病毒（RSV)RSV)基因组结构图基因组结构图 病毒癌基因与正常细胞中的原癌基因同源病毒癌基因与正常细胞中的原癌基因同源第10页，讲稿共155张，创作于星期二 病病毒毒癌癌基基因因致致癌癌机机制制第11页，讲稿共155张，创作于星期二l l19641964196
8、41964年年年年H.M.TeminH.M.TeminH.M.TeminH.M.Temin认为，认为，认为，认为，RSVRSVRSVRSV的生活周期中存在着的生活周期中存在着前病毒前病毒前病毒前病毒（provirusprovirus）的）的）的）的DNADNADNADNA中间产物阶段，中间产物阶段，DNADNA前病毒含有前病毒含有RNARNARNARNA病毒基因组的全部信息。病毒基因组的全部信息。病毒基因组的全部信息。病毒基因组的全部信息。l l子代病毒子代病毒RNARNARNARNA是以前病毒是以前病毒是以前病毒是以前病毒DNADNA为模版合成的。前病毒可为模版合成的。前病毒可整合到宿主细胞
9、基因组中。通过病毒的诱导，正常细整合到宿主细胞基因组中。通过病毒的诱导，正常细胞可胞可转化转化转化转化成肿瘤细胞。成肿瘤细胞。l l19701970年年TeminTemin实验室和实验室和Baltimove Baltimove 实验室分别发现实验室分别发现实验室分别发现实验室分别发现RSVRSV病毒粒子中含有病毒粒子中含有病毒粒子中含有病毒粒子中含有反转录酶反转录酶反转录酶反转录酶。这一结果使。这一结果使Temin Temin Temin Temin 的的的的“前病前病毒毒”假想得到了证实。假想得到了证实。l l19751975年年年年TeminTeminTeminTemin、Baltimov
10、eBaltimove和和和和DulbaccoDulbaccoDulbaccoDulbacco因此获诺贝尔生理因此获诺贝尔生理和医学奖。和医学奖。第12页，讲稿共155张，创作于星期二The Nobel Prize in Physiology or Medicine 1975 The interaction between tumor viruses and the genetic material of the cell第13页，讲稿共155张，创作于星期二David B BaltimoreUSAMassachusetts Institute ofTechnology(MIT)Cambridg
11、e,MA,USAB:1938第14页，讲稿共155张，创作于星期二Renato DulbeccoUSAImperial Cancer ResearchFund LaboratoryLondon,United KingdomB:1914(in Catanzaro,Italy)第15页，讲稿共155张，创作于星期二Howard Martin TeminUSAUniversity of WisconsinMadison,WI,USAB:1934D:1994第16页，讲稿共155张，创作于星期二BishopBishop和和VarmuVarmus s等人于等人于19801980年提出了年提出了癌基因假说
12、癌基因假说，认为认为RousRous鸡肉瘤病毒的致癌能力与病毒基因组的鸡肉瘤病毒的致癌能力与病毒基因组的单个基因有关，即单个基因有关，即srcsrc基因。基因。srcsrc基因本是正常细胞基因组的一部分基因本是正常细胞基因组的一部分(原癌基因），原癌基因），被病毒被病毒“劫持劫持”后，病毒则具有致癌能力。后，病毒则具有致癌能力。原癌基因在正常细胞中的地位：调控细胞的分原癌基因在正常细胞中的地位：调控细胞的分裂和生长。裂和生长。肿瘤细胞中癌基因的变化：过分活跃或突变，肿瘤细胞中癌基因的变化：过分活跃或突变，使其编码产物改变。使其编码产物改变。BishopBishop和和VarmusVarmus获
13、获19891989年诺贝尔生理学和医学奖年诺贝尔生理学和医学奖第17页，讲稿共155张，创作于星期二The Nobel Prize in Physiology or Medicine 1989 The cellular origin of retroviral oncogenes第18页，讲稿共155张，创作于星期二J.Michael BishopUSAUniversity of CaliforniaSchool MedicineSan Francisco,CA,USAB:1936第19页，讲稿共155张，创作于星期二Harold E.VarmusUSAUniversity of Califo
14、rniaSchool of MedicineSan Francisco,CA,USAB:1939第20页，讲稿共155张，创作于星期二Press Release:The 1989 Nobel Prize in Physiology or MedicineNOBELFRSAMLINGEN KAROLINSKA INSTITUTETTHE NOBEL ASSEMBLY AT THE KAROLINSKA INSTITUTE9October1989The Nobel Assembly at Karlinska InstitutehastodaydecidedtoawardtheNobelPrizei
15、nPhysiologyorMedicinefor1989jointlytoJ.Michael Bishop and Harold E.Varmusfortheirdiscoveryofthecellularoriginofretroviraloncogenes.Press Release第21页，讲稿共155张，创作于星期二SummaryThediscoveryawardedwiththisyearsNobelPrizeinPhysiologyorMedicineconcernstheidentificationofalargefamilyofgeneswhichcontrolthenorma
16、lgrowthanddivisionofcells.Distur-bancesinoneorsomeoftheseso-calledoncogenes(Gknco(s)Bulk,mass)canleadtotransformationofanormalcellintoatumorcellandresultincancer.Michael BishopandHarold Varmususedanoncogenicretrovirustoidentifythegrowth-controllingoncogenesinnormalcells.In1976theypublishedtheremarka
17、bleconclusionthattheoncogeneinthevirusdidnotrepresentatrueviralgenebutinsteadwasanormalcellulargene,whichthevirushadacquiredduringreplicationinthehostcellandthereaftercarriedalong.第22页，讲稿共155张，创作于星期二BishopsandVarmusdiscoveryofthecellularoriginofretroviraloncogeneshashadanextensiveinfluenceonthedevel
18、opmentofourknowledgeaboutmechanismsfortumordevelopment.Untilnowmorethan40differentoncogeneshavebeendemonstrated.Thediscoveryhasalsowidenedourinsightintothecomplicatedsignalsystemswhichgovernthenormalgrowthofcells.Cellular Oncogenes Discovered by the Use of RetrovirusThetermoncogenewasintroducedinthe
19、middleofthe1960stodenotespecialpartsofthegeneticmaterialofcertainviruses.Itwasbelievedthatthispartofthegeneticmaterialcoulddirectthetransformationofanormalcellintoatumorcellundertheinfluenceofotherpartsoftheviralgeneticmaterial,alternativelyviachemicalorphysicaleffects.Thefavouritetheoryofthetimewas
20、thatvirus-mediatedcell-to-celltransmittanceofoncogeneswastheoriginofallformsofcancer.Thisviewwaslaterproventobeincorrect.第23页，讲稿共155张，创作于星期二Theoriginaldiscoveryofanoncogenicviruswasmadein1916byPeyton RousworkingattheRockefellerInstituteinNewYork.FiftyyearslaterRousreceivedtheNobelPrizeinPhysiologyor
21、Medicine.Rousvirus,astheinfectiousagentlaterwasnamed,isamemberofalargevirusfamilynamedretroviruses.ThegeneticmaterialofthesevirusesisRNA(ribonucleicacid).ThisRNAcanbetranscribedintoDNA(deoxyribonucleicacid)byauniqueenzymeinthevirus,reversetranscriptase.The1975NobelPrizeinPhysiologyorMedicinewasaward
22、edtoDavidBaltimore,RenatoDulbeccoandHawardTeminpartlyforthediscoveryofthisenzyme.ReversetranscriptionofthegeneticmaterialofthevirusintoDNAhastheimportantconsequencethatitcanbecomeintegratedintothechromosomalDNAinthecells.ItwasthroughinvestigationsofRousvirusthatthisyearslaureatesMichael BishopandHar
23、old Varmusin1975coulddemonstratethetrueoriginofoncogenes.TheyusedonevariantofRousviruswhichcontainedanoncogenicgene(Figure1)andanothervariantwhichlackedthisgene.第24页，讲稿共155张，创作于星期二Byuseofthesevirusestheymanagedtoconstructanucleicacidprobewhichselectivelyidentifiedtheoncogene.Thisprobewasusedtosearch
24、forthecorrespondinggeneticmaterialinDNAfromdifferentcells.Itwasthenfoundthatoncogene-likematerialcouldbedetectedindifferentspeciesthroughouttheanimalkingdom,infacteveninsimpleorganismscomprisingonlyafewcells.Furthermore,itwasshownthatthegenehadafixedpositioninthechromosomesofacertainspecies,andthatt
25、hegene,whenitconstitutedpartofthecellulargeneticmaterial,wasdividedintofragments(amosaicgene)(Figure1).Figure 1.Thedifferencebetweenanoncogeneinavirusandinacell.Inretrovirusescausingtumorsthereisaseparatesegmentoftransformingnucleicacidwhichhasbeenderivedfromacell.Thecellulargeneissplit(amosaicgene)
26、whereastheoncogeneinthevirusiscontinuous.第25页，讲稿共155张，创作于星期二Thesefindingsledtotheremarkableconclusionthattheoncogeneinthevirusdidnotrepresentatrueviralgenebutacellulargenewhichthevirushadpickedupfarbackduringitsreplicationincellsandcarriedalong.Thiscellulargenewasfoundtohaveacentralfunctioninthecell
27、s.Itcontrolledtheirgrowthanddivision.Throughthesestudiesoftheabnormal,i.e.thediseasedstate,itwaspossibletoelucidatecriticalnormalcellularfunctions-anotuncommonsituationinbiomedicalresearch.Theoriginaldiscoveryofacellularoncogeneledtoanintensivesearchforfurthersimilargenes.Theexplosivedevelopmentofth
28、isfieldofresearchhasledtotheidentificationofmorethan40differentoncogeneswhichdirectdifferenteventsinthecomplexsignalsystemsthatregulatethegrowthanddivisionofcells.Changesinanyoneormoreoftheseoncogenesmayleadtocancer.第26页，讲稿共155张，创作于星期二Balanced Cellular Interactions-A Biological WonderSymmetricalanda
29、symmetrical,multicellularstructuresdevelopfromthefertilizedovumbyaprocessofdifferentiationaboutwhichonlylimitedknowledgeisavailable.Inthefullydevelopedindividualcarefullybalancedconditionsprevail.Damageofanorganelicitssophisticatedrepairprocesseswhichleadtorestitutionoftheoriginalconditionoftheorgan
30、.However,ifasinglecellescapesthenetworkofgrowthcontroltheresultmaybeanabnormallocalproliferationofcellsorintheworstcaseacancerimplyingthedisseminationofcellsrunningamok.Thedevelopmentofacancerisacomplicatedprocessinvolvingseveralconsecutivechangesofthegeneticmaterial.Studiesofcellulargenes(proto-onc
31、ogenes)correspondingtotheviraloncogenes,hasstartedtoshedlightontheintricatesystemswhichcontrolnormalcellulargrowthanddivision.第27页，讲稿共155张，创作于星期二Cellular Oncogene Products Constitute Links in Signal Chains which Regulate Growth and Division of CellsTheregulationofgrowthanddivisionofcellshasturnedout
32、tobemuchmorecomplicatedthanoriginallybelieved.Cellularoncogeneproductswithdifferentpropertiesactindifferentpositionsofelaboratesignalsystems(Figure2).Inordertotransmitsignalsfromonecelltotheotherorfromonecelltoitselftherearegrowthfactors.Thesefactorsappearinthefluidssurroundingcells.Thereareexamples
33、ofoncogeneproducts,viz.proteinsproducedinthecytoplasm,whichcanactasgrowthfactors.Thus,itwasfoundthattheproductofthesis1)genewascloselyrelatedtoapreviouslyidentifiedgrowthfactorPDGF(PlateletDerivedGrowthFactor).第28页，讲稿共155张，创作于星期二Figure 2.Oncogene products are links in signal chains that stretch from
34、 the cell surface to the genetic material in the cell nucleus.This chain is composed of(1)growth factors,(2)growth factor receptors,(3)signal transducing proteins in cell membranes,(4)phosphokinases in the cytoplasm and(5)proteins transported from the cytoplasm into the nucleus where they bind to DN
35、A.The localization of different oncogene products(Sis,ErbB,Ras,Src,Myc)is schematically indicated.第29页，讲稿共155张，创作于星期二In order for a growth factor to be able to interact with a cell there has to be membrane structures,receptors,to which they can bind.There are several oncogene products which represen
36、t receptors in the cytoplasmic membrane of the cells,e.g.ErbA,Fms,Kit.These receptors have a unique enzymatic activity.They are so-called kinases with a capacity to phosphorylate(=add a phosphate group)the amino acid tyrosine.There are two more groups of oncogene products with phosphokinase activity
37、;firstly tyrosine/phospho-kinase which lack receptor function and is located at the inside of the cytoplasmic membrane,and secondly serine/threonine phosphokinase which is found in the cytoplasm.Thus,oncogene products function as links in signal chains stretching from the surface of the cell to the
38、genetic material in the nucleus.In the cytoplasm there is one more group of oncogene products.These are called Ras and are related to important cellular signal factors called G-proteins.Finally,there is a large number of oncogene products which are located in the nucleus of the cell,i.e.Myc,Myb,Fos,
39、ErbA and others.These products direct the transcription of DNA into RNA and therefore play a critical role in the selection of proteins to be synthesized by the cell.第30页，讲稿共155张，创作于星期二Cancer-A Complex,Biological Sequence of EventsChanges in the genetic material constitute the basis for the developm
40、ent of all cancer.Generally there are several consecutive such changes which influence different steps in the signal chains described above.Therefore,one should priori not expect to find one single clue to the mechanism of origin of cancer.However,application of the expanding knowledge in the oncoge
41、ne field allows us to start comprehending the disharmonic orchestration behind abnormal cellular growth.It is conceptually incorrect to speak about cancer genes.However,historical circumstances explain why the oncogene terminology was introduced before a designation of the corresponding normal cellu
42、lar genes was proposed.From the point of view of cancer the important matter is to compare oncogenes in normal cells and in tumor cells.第31页，讲稿共155张，创作于星期二Oncogenes as a Cause of CancerThe majority of oncogenes have been discovered in experimental studies using retroviruses.However,in a few cases on
43、cogenes were identified bythe use of an alternative technique,i.e.genetic material was isolated from tumor cells of non-viral origin and transferred(transfected)to other cells prapagated in culture.The cells receiving the DNA changed growth pattern,and further characterization of the transfected gen
44、etic material revealed the presence of oncogenes.Two principally different forms of activation of oncogenes can be distinguished.Firstly,the normal cellular oncogene is hyperactive,and secondly the oncogene product is altered so that it can no longer be regulated in a normal way.There are several ex
45、amples of these types of activation of oncogenes.The discovery of oncogenes was as mentioned originally made by the use of retroviruses.This infers that genetic control elements in the virus itself can be responsible for the abnormal expression of the oncogene.However,in many cases it was found that
46、 alterations of the transferred oncogene contributed to its accentuated expression.第32页，讲稿共155张，创作于星期二There are retroviruses which lack oncogenes but still can induce cancer.This is due to the fact that the virus has inserted its genetic material(in the form of DNA)very close to a normally occurring
47、 oncogene in the genetic material of the cell.This may result in an increased turn-over of the oncogene which may lead to abnormal cellular growth.The corresponding phenomenon can also occur in the absence of retroviruses.In this case there is a reorgani-zation of the genetic material in the cell.Su
48、ch a reorganization may occur within a single chromosome or by exchange of material between chromosomes.Repeated copying of a normal oncogene can lead to its amplification in the chromosome and consequently to increased amounts of the oncogene product.In certain brain tumors,glioblastomas,an amplifi
49、ed erbB-gene has been found,and a correspondingly increased neu-gene activity was shown in some forms of breast cancer.The same effect can be seen when there is a reciprocal exchange of segments between chromosomes(translocation).Thus the normal myc-gene on chromosome 8 has been translocated to chro
50、mosome 14 in many patients with Burkitts lymphomas(Figure 3).The insertion of the myc-gene containing chromosome segment is such that it becomes located close to hyperactive genes directing the synthesis of antibody protein.As a 第33页，讲稿共155张，创作于星期二consequence the myc-gene becomes activated.Chromosom