分子生物学原理(癌症)课件

v-Srcproteinisaconstitutivelyactivemutantformofc-Srcprotein,aprotein-tyrosinekinaseIncellscontaininganintegratedRSVgenome:a.v-srctranscribedatinappropriatelyhighratelevel,b.Theunregulatedactivityofv-Srcproteincausescontinuosandinappropriatephosphorylationoftargetproteins.V-srcisadominantgain-of-functionmutantofc-src,sincev-srccaninducecelltransformationinthepresenceofthenormalc-srcproto-oncogene.

Manyotheroncogenesderivedfromcellularproto-oncogeneshavebeenfoundindifferentretroviruses,implyingthatthenormalvertebrategenomecontainsmanypotentialcancer-causinggenes.

TheDNAtransfectionexperimenthasledtothemolecularcloningofarasgenewithasinglepointmutationinhumanbladdertumors,adominantgain-of-functiononcogene.Thisoncogene,designatedHa-ras,alsoispresentinHarveysarcomavirus,aretrovirus.Similarexperimentshaveledtothecloningofnumerousoncogenesfromtumor-cellDNA.Manyofthesecancer-causinggenesarealsofoundinvariousanimalretroviruses.Slow-actingcarcinogenicretrovirusescanactivatecellularproto-oncogenesRoussarcomavirusinducestumorswithindayswhilemostoncogenicretrovirusesinducecanceronlyafteraperiodofmonthsoryears.RSVcarriesthev-srconcogeneinitsgenomewhilemostoncogenicretroviruseslackanoncogeneThesiteofintegrationinthecellsfromtumorscausedbyavianleukosisvirusesisnearthec-mycgenesuggestedthattheseslow-actingvirusescausediseasebyactivatingexpressionofc-Myc.Thesevirusesactslowlybothbecausseintegrationnearc-mycisarandom,rareeventandbecauseadditionalmutantshavetooccurbeforeafull-fledgedtumorbecomesevident.Thesemechanismsofoncogeneactivation--calledpromoterinsertionandenhancerinsertion--operateinavarietyofoncogenesandhavebeenimplicatedinmanyanimaltumorscausedbyslow-actingretrovviruses.Innaturalbirdandmousepopulations,slow-actingretrovirusesaremuchmorecommonthanoncogene-containingretrovirusessuchasRoussarcomavirus.Thus,insertionaloncogeneactivationisprobablythemajormechanismwherebyretrovirusescausecancer.Loss-of-functionmutationsintumor-suppressorgenesareoncogenicTumor-suppressorgenesgenerallyencodeproteinsthatinonewayoranotherinhibitcellproliferation.Lossofoneormoreofthese“brakes”contributestothedevelopmentofmanycancers.Fivebroadclassesofproteinsaregenerallyrecognizedasbeingencodedbytumor-suppressorgenesSincegenerallyonecopyofatumor-suppressorgenesufficestocontrolcellproliferation,bothallelesofatumor-suppressorgenemustbelostorinactivatedinordertopromotetumordevelopment.Oncogenicloss-of-functionmutationsintumor-suppressorgenesactrecessively.Tumor-suppressorgenesinmanycancershavedeletionsorpoint-mutationsthatpreventproductionofanyproteinorleadtoproductionofanonfunctionalprotein.Thefirsttumor-suppressorgenewasidentifiedinpatientswithinheritedretinoblastomaChildrenwithhereditaryretinoblastomainheritasingledefectivecopyoftheRBgene,sometimesseenasasmalldeletiononchromosome13.Theydevelopretinaltumorsearlyinlifeandgenerallyinbotheyes.Eachtumorthatdevelopsisderivedfromasingletransformedcell.Thedevelopingretinacontainsabout4x106cells,butonly1in106cellsactuallygivesrisesrisetoatumorcell.ThisfindingshowsthatthedefectiveRBalleleisactingrecessivelyatthecellularlevel,andthatothergeneticeventsareneededtobringonthetransformedstate.MolecularcloningoftheRBgeneestablishedthatindividualswithhereditaryretinoblastomainheritedonenormalandonemutantRBallele.Onaverage,theywillpassonthemutantalleletohalftheirchildrenandthenormalalleletotheotherhalf.ChildrenwhoinheritthenormalallelearenormaliftheirotherparenthastwonormalRBalleles.However,thosewhoinheritthemutantallelehavethesameenhancedpredispositiontodevelopretinaltumorsastheiraffectedparent,eventhoughtheyinheritanormalRBallelefromother,normalparent.Thushereditaryretinoblastomaisinheritedasanautosomaldominanttrait.

Lossofheterozygosityoftumor-suppressorgenesoccursbymitoticrecombinationorchromosomemis-segregationVirus-encodedactivatorsofgrowth-factorreceptorsactasoncoproteinsProliferation,survival,anddifferentiationoferythroidprogenitorsintomatureredcellsabsolutelyrequiresEpo(madebycellsinkidney)andcorrespondingEporeceptor.SFFVencodesamutantretrovirusenvelopeglycoprotein,termedgp55,thatismissingmuchofthenormalextracellulardomainandallthecytosolicdomain.IthasacquiredtheremarkableabilitytobindtoandactivateEporeceptorsexpressedinthesamecell.Byinappropriatelyandcontinuouslystimilatingtheproliferationoferythroidprogenitors,gp55expressioninducespolycythemia.MutationsleadingtooverexpressionofanormalreceptorproteinalsocanbeoncogenicForinstance,manyhumanbreastcancersoverexpressanotherwisenormalHer2receptor.DeletionofthePTENphosphataseisafrequentoccurrenceinhumantumorsSincemanyproto-oncogenesareproteinkinases,ithaslongbeenspeculatedthatproteinphosphatasesmightfunctionastumorssuppressor.Onlyinthepastfewyearswasthefirstphosphatase,PTEN,identifiedasatumorsuppressor;PTENisdeletedinmultipletypesofadvancedhumancancers.Inappropriateexpressionofnucleartranscriptionfactorscaninducetransformation3.4Mutationscausing

lossofcell-cyclecontrolTheentryofcellsaroundthecyclearepreciselycontrolledevents.OnceacellprogressespastacertainpointinlateG1,calledtherestrictionpoint,itbecomesirreversiblycommitedtoenteringtheSphaseandreplicatingitsDNAcyclins,cyclin-dependentkinases(Cdks),andtheRbproteinareallelementsofthecontrolsystemthatregulatepassagethroughtherestrictionpoint.Alteredregulationofexpressionofatleastonecyclinaswellasmutationofseveralproteinsthatnegativelyregulatepassagethroughtherestrictionpointcanbeoncogenic.Lossofp16wouldminiccyclinD1overexpression,leadingtoRbhyperphosphorylationandreleaseofactiveE2Ftranscriptionfactor.LossofRbfunctionleadstoinductionofmanytypesofcancers,childhoodretinoblastomamostnotably.LossofTGFßsignalingcontributestoabnormalcellproliferationandmalignancyTumor-derivedgrowthfactorß(TGF

ß)issecretedbymostbodycellsandhasadiverserangeoffunctions.MostrelevantistheabilityofTGFßtoinhibitthegrowthofmanytypescells,includingmostepithelialandimmunesystemcells.LossofTGFßmediatedgrowthinhibitioncontributestothedevelopmentandprogression