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1、关于癌基因抑癌基因与生长因子现在学习的是第1页，共155页 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、成熟和衰老，促进分化、成熟和衰老，最后凋亡。最后凋亡。这两类基因中任何一种或它们共同的变化，即有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可能引起细胞增殖失控导致肿瘤的发生。现在学习的是第2页，共155页癌基因与抑癌基因的作用机制涉及基因表达癌基因与抑癌基因的作用机制涉及基
2、因表达调控及细胞分裂、分化。调控及细胞分裂、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子，通过细胞内信息传递系统刺激细胞增殖。殖。肿瘤的发生与癌基因、抑癌基因和生长因子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。三者的关系密切相关。现在学习的是第3页，共155页第一节 癌基因现在学习的是第4页，共155页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传性状发生改变的基因。l
3、癌基因可分为两大类：一类是致瘤病毒中能在体内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，即病毒癌诱发肿瘤并在体外引起细胞转化的基因，即病毒癌基因（基因（viral oncogene,v-oncviral oncogene,v-onc）；另一类是存在于细）；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）胞基因组中、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，当受到致癌因素作用被活化而导致细胞恶变的基因，即原癌基致癌因素作用被活化而导致细胞恶变的基因，即原癌基因（
4、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）概念现在学习的是第5页，共155页 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。养细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DNADNA病毒病毒和和RNARN
5、A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是逆转录病毒）中的、能使靶细胞发生恶性转化的基因。转化的基因。现在学习的是第6页，共155页 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，野生棉尾兔的皮肤肿瘤也可借助无细胞
6、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，被状态，被化学因子、病毒等唤醒后，变的无法无天。化学因子、病毒等唤醒后，变的无法无天。lRousRous提出病毒致癌理论：提出病毒致癌理论：即传播肿瘤的无细胞滤液中含即传播肿瘤的无细胞滤液中含的是病毒。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。癌基因的发现现在学习的是第7页，共155页The Nobel Prize in Physiolo
7、gy or Medicine 1966 Tumor-inducing viruses现在学习的是第8页，共155页Peyton RousUSARockefeller UniversityNew York,NY,USAB:1879D:1970现在学习的是第9页，共155页鸡肉瘤病毒（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现在学习的是第10页，共155页 病病毒毒癌癌基基因因致致癌癌机机制制现在学习的是第11页，共155页l l1964196419641964年年年年H.M.TeminH.M.TeminH.M.
8、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（provirusprovirusprovirusprovirus）的）的）的）的DNADNADNADNA中间产物阶段，中间产物阶段，中间产物阶段，中间产物阶段，DNADNADNADNA前病毒含有前病毒含有前病毒含有前病毒含有RNARNARNARNA病病病病毒基因组的全部信息。毒基因组的全部信息。毒基因组的全部信息。毒基因组的全部信息。l l子代病毒子代病毒子代病毒子代病毒RNARNARNARNA是以前病毒是以前病毒是以前病
9、毒是以前病毒DNADNADNADNA为模版合成的。前病毒可为模版合成的。前病毒可为模版合成的。前病毒可为模版合成的。前病毒可整合到宿主细胞基因组中。通过病毒的诱导，正常细胞整合到宿主细胞基因组中。通过病毒的诱导，正常细胞整合到宿主细胞基因组中。通过病毒的诱导，正常细胞整合到宿主细胞基因组中。通过病毒的诱导，正常细胞可可可可转化转化转化转化成肿瘤细胞。成肿瘤细胞。成肿瘤细胞。成肿瘤细胞。l l1970197019701970年年年年TeminTeminTeminTemin实验室和实验室和实验室和实验室和Baltimove Baltimove Baltimove Baltimove 实验室分别发现
10、实验室分别发现实验室分别发现实验室分别发现RSVRSVRSVRSV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。这一结果使。这一结果使Temin Temin Temin Temin 的的的的“前前前前病毒病毒病毒病毒”假想得到了证实。假想得到了证实。假想得到了证实。假想得到了证实。l l1975197519751975年年年年TeminTeminTeminTemin、BaltimoveBaltimoveBaltimoveBaltimove和和和和DulbaccoDulbaccoDulbaccoDulbacco因此获诺贝尔生因此
11、获诺贝尔生因此获诺贝尔生因此获诺贝尔生理和医学奖。理和医学奖。理和医学奖。理和医学奖。现在学习的是第12页，共155页The Nobel Prize in Physiology or Medicine 1975The Nobel Prize in Physiology or Medicine 1975 The interaction between tumor viruses and the genetic material of the cell现在学习的是第13页，共155页David B BaltimoreUSAMassachusetts Institute ofTechnology(M
12、IT)Cambridge,MA,USAB:1938现在学习的是第14页，共155页Renato DulbeccoUSAImperial Cancer ResearchFund LaboratoryLondon,United KingdomB:1914(in Catanzaro,Italy)现在学习的是第15页，共155页Howard Martin TeminUSAUniversity of WisconsinMadison,WI,USAB:1934D:1994现在学习的是第16页，共155页BishopBishop和和VarmuVarmus s等人于等人于19801980年提出了年提出了癌基因
13、假说癌基因假说，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：调控细胞的分裂原癌基因在正常细胞中的地位：调控细胞的分裂和生长。和生长。肿瘤细胞中癌基因的变化：过分活跃或突变，使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。其编码产物改变。BishopBishop和和VarmuVarmus
14、 s获获19891989年诺贝尔生理学和医学奖年诺贝尔生理学和医学奖现在学习的是第17页，共155页The Nobel Prize in Physiology or Medicine 1989The Nobel Prize in Physiology or Medicine 1989 The cellular origin of retroviral oncogenes现在学习的是第18页，共155页J.Michael BishopUSAUniversity of CaliforniaSchool MedicineSan Francisco,CA,USAB:1936现在学习的是第19页，共15
15、5页Harold E.VarmusUSAUniversity of CaliforniaSchool of MedicineSan Francisco,CA,USAB:1939现在学习的是第20页，共155页Press Release:The 1989 Nobel Prize in Physiology or MedicineNOBELFRSAMLINGEN KAROLINSKA INSTITUTETTHE NOBEL ASSEMBLY AT THE KAROLINSKA INSTITUTE9October1989The Nobel Assembly at Karlinska Institut
16、ehastodaydecidedtoawardtheNobelPrizeinPhysiologyorMedicinefor1989jointlytoJ.Michael Bishop and Harold E.Varmusfortheirdiscoveryofthecellularoriginofretroviraloncogenes.Press Release现在学习的是第21页，共155页SummaryThediscoveryawardedwiththisyearsNobelPrizeinPhysiologyorMedicineconcernstheidentificationofalarg
17、efamilyofgeneswhichcontrolthenormalgrowthanddivisionofcells.Distur-bancesinoneorsomeoftheseso-calledoncogenes(Gknco(s)Bulk,mass)canleadtotransformationofanormalcellintoatumorcellandresultincancer.Michael BishopandHarold Varmususedanoncogenicretrovirustoidentifythegrowth-controllingoncogenesinnormalc
18、ells.In1976theypublishedtheremarkableconclusionthattheoncogeneinthevirusdidnotrepresentatrueviralgenebutinsteadwasanormalcellulargene,whichthevirushadacquiredduringreplicationinthehostcellandthereaftercarriedalong.现在学习的是第22页，共155页BishopsandVarmusdiscoveryofthecellularoriginofretroviraloncogeneshasha
19、danextensiveinfluenceonthedevelopmentofourknowledgeaboutmechanismsfortumordevelopment.Untilnowmorethan40differentoncogeneshavebeendemonstrated.Thediscoveryhasalsowidenedourinsightintothecomplicatedsignalsystemswhichgovernthenormalgrowthofcells.Cellular Oncogenes Discovered by the Use of RetrovirusTh
20、etermoncogenewasintroducedinthemiddleofthe1960stodenotespecialpartsofthegeneticmaterialofcertainviruses.Itwasbelievedthatthispartofthegeneticmaterialcoulddirectthetransformationofanormalcellintoatumorcellundertheinfluenceofotherpartsoftheviralgeneticmaterial,alternativelyviachemicalorphysicaleffects
21、.Thefavouritetheoryofthetimewasthatvirus-mediatedcell-to-celltransmittanceofoncogeneswastheoriginofallformsofcancer.Thisviewwaslaterproventobeincorrect.现在学习的是第23页，共155页Theoriginaldiscoveryofanoncogenicviruswasmadein1916byPeyton RousworkingattheRockefellerInstituteinNewYork.FiftyyearslaterRousreceive
22、dtheNobelPrizeinPhysiologyorMedicine.Rousvirus,astheinfectiousagentlaterwasnamed,isamemberofalargevirusfamilynamedretroviruses.ThegeneticmaterialofthesevirusesisRNA(ribonucleicacid).ThisRNAcanbetranscribedintoDNA(deoxyribonucleicacid)byauniqueenzymeinthevirus,reversetranscriptase.The1975NobelPrizein
23、PhysiologyorMedicinewasawardedtoDavidBaltimore,RenatoDulbeccoandHawardTeminpartlyforthediscoveryofthisenzyme.ReversetranscriptionofthegeneticmaterialofthevirusintoDNAhastheimportantconsequencethatitcanbecomeintegratedintothechromosomalDNAinthecells.ItwasthroughinvestigationsofRousvirusthatthisyearsl
24、aureatesMichael BishopandHarold Varmusin1975coulddemonstratethetrueoriginofoncogenes.TheyusedonevariantofRousviruswhichcontainedanoncogenicgene(Figure1)andanothervariantwhichlackedthisgene.现在学习的是第24页，共155页Byuseofthesevirusestheymanagedtoconstructanucleicacidprobewhichselectivelyidentifiedtheoncogene
25、.ThisprobewasusedtosearchforthecorrespondinggeneticmaterialinDNAfromdifferentcells.Itwasthenfoundthatoncogene-likematerialcouldbedetectedindifferentspeciesthroughouttheanimalkingdom,infacteveninsimpleorganismscomprisingonlyafewcells.Furthermore,itwasshownthatthegenehadafixedpositioninthechromosomeso
26、facertainspecies,andthatthegene,whenitconstitutedpartofthecellulargeneticmaterial,wasdividedintofragments(amosaicgene)(Figure1).Figure 1.Thedifferencebetweenanoncogeneinavirusandinacell.Inretrovirusescausingtumorsthereisaseparatesegmentoftransformingnucleicacidwhichhasbeenderivedfromacell.Thecellula
27、rgeneissplit(amosaicgene)whereastheoncogeneinthevirusiscontinuous.现在学习的是第25页，共155页Thesefindingsledtotheremarkableconclusionthattheoncogeneinthevirusdidnotrepresentatrueviralgenebutacellulargenewhichthevirushadpickedupfarbackduringitsreplicationincellsandcarriedalong.Thiscellulargenewasfoundtohaveace
28、ntralfunctioninthecells.Itcontrolledtheirgrowthanddivision.Throughthesestudiesoftheabnormal,i.e.thediseasedstate,itwaspossibletoelucidatecriticalnormalcellularfunctions-anotuncommonsituationinbiomedicalresearch.Theoriginaldiscoveryofacellularoncogeneledtoanintensivesearchforfurthersimilargenes.Theex
29、plosivedevelopmentofthisfieldofresearchhasledtotheidentificationofmorethan40differentoncogeneswhichdirectdifferenteventsinthecomplexsignalsystemsthatregulatethegrowthanddivisionofcells.Changesinanyoneormoreoftheseoncogenesmayleadtocancer.现在学习的是第26页，共155页Balanced Cellular Interactions-A Biological Wo
30、nderSymmetricalandasymmetrical,multicellularstructuresdevelopfromthefertilizedovumbyaprocessofdifferentiationaboutwhichonlylimitedknowledgeisavailable.Inthefullydevelopedindividualcarefullybalancedconditionsprevail.Damageofanorganelicitssophisticatedrepairprocesseswhichleadtorestitutionoftheoriginal
31、conditionoftheorgan.However,ifasinglecellescapesthenetworkofgrowthcontroltheresultmaybeanabnormallocalproliferationofcellsorintheworstcaseacancerimplyingthedisseminationofcellsrunningamok.Thedevelopmentofacancerisacomplicatedprocessinvolvingseveralconsecutivechangesofthegeneticmaterial.Studiesofcell
32、ulargenes(proto-oncogenes)correspondingtotheviraloncogenes,hasstartedtoshedlightontheintricatesystemswhichcontrolnormalcellulargrowthanddivision.现在学习的是第27页，共155页Cellular Oncogene Products Constitute Links in Signal Chains which Regulate Growth and Division of CellsTheregulationofgrowthanddivisionofc
33、ellshasturnedouttobemuchmorecomplicatedthanoriginallybelieved.Cellularoncogeneproductswithdifferentpropertiesactindifferentpositionsofelaboratesignalsystems(Figure2).Inordertotransmitsignalsfromonecelltotheotherorfromonecelltoitselftherearegrowthfactors.Thesefactorsappearinthefluidssurroundingcells.
34、Thereareexamplesofoncogeneproducts,viz.proteinsproducedinthecytoplasm,whichcanactasgrowthfactors.Thus,itwasfoundthattheproductofthesis1)genewascloselyrelatedtoapreviouslyidentifiedgrowthfactorPDGF(PlateletDerivedGrowthFactor).现在学习的是第28页，共155页Figure 2.Oncogene products are links in signal chains that
35、 stretch from 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 th
36、ey bind to DNA.The localization of different oncogene products(Sis,ErbB,Ras,Src,Myc)is schematically indicated.现在学习的是第29页，共155页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 whic
37、h represent 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 phosphokinas
38、e activity;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 ce
39、ll to the 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.My
40、c,Myb,Fos,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.现在学习的是第30页，共155页Cancer-A Complex,Biological Sequence of EventsChanges in the genetic material constitute the basis for the d
41、evelopment 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
42、 oncogene 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 norma
43、l cellular genes was proposed.From the point of view of cancer the important matter is to compare oncogenes in normal cells and in tumor cells.现在学习的是第31页，共155页Oncogenes as a Cause of CancerThe majority of oncogenes have been discovered in experimental studies using retroviruses.However,in a few case
44、s oncogenes 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
45、 genetic 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 severa
46、l examples 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
47、that alterations of the transferred oncogene contributed to its accentuated expression.现在学习的是第32页，共155页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 occurrin
48、g 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.S
49、uch 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 amplif
50、ied 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 chr