The first 30 years of p53Word下载.docx
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1InstituteforAdvancedStudy,Princeton,NJ
2WeizmannInstituteofScience,Rehovot,Israel
Thepublisher'
sfinaleditedversionofthisarticleisavailableatNatRevCancer
SeeotherarticlesinPMCthatcitethepublishedarticle.
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oAbstract
oPrelude:
tumorviruses,
oncogenesandtheroadtop53
oTheearlyyears:
p53isanoncogene?
oGrandentryintothetumorsuppressormainstage
oHowdoesp53doit?
op53andMDM2:
inandoutofloops
oWhatisthisgoodfor?
p53andcancertherapy
oRestoringp53activity
oTheFuture
oReferences
Abstract
Thirtyyearsago,p53wasdiscoveredasacellularpartnerofSV40LargeTumorAntigen,theoncoproteinofthistumorvirus.Thefirstdecadeofp53researchsawthecloningofp53DNAandtherealizationthatp53isnotanoncogenebutatumorsuppressorthatisveryfrequentlymutatedinhumancancer.Intheseconddecade,thefunctionofp53,atranscriptionfactorinducedbystress,resultingincellcyclearrest,apoptosisandsenescence,wasuncovered.Initsthirddecadenewfunctionswererevealed,includingregulationofmetabolicpathwaysandcytokinesrequiredforembryoimplantation.Thefourthdecademayseenewp53-baseddrugstotreatcancer.Whatisnextisanybody’sguess.
Bynow,anybodywithinterestincancerresearchisalreadywellawareoftheexistenceofp53anditsrelevancetopracticallyeveryaspectoftumorbiology1.Itisimpossibletooverlooktheprominenceofp53:
withnearly50,000PubMed-listedpublicationssofarandasteadyflowofnewoneshittingthecyberspaceeveryweek,p53isundoubtedlyoneofthemostextensivelystudiedgenesandproteins.EveryotheryearhundredsofscientistsgatherforanInternationalp53Workshoptodiscussasinglegeneandprotein.However,thenotionthatp53isapivotaltumorsuppressorandamajormainstayinourbody’snaturalanti-cancerdefense,nowtakenforgranted,didnotcomeeasily.Whendiscovered30yearsago,p53waslittlemorethanjustanother“interesting”proteinthatmostcancerresearchersdidnotconsiderworthyofmuchattention,letaloneofinvestmentofresearchtimeandresources.Unlikewell-behavedoncogenes,whichwereoftenbroughtintothemainstageshortlyaftertheirdiscovery,p53receivedrelativelylittleattentioninitsfirstyears.Theroadleadingtop53’seventualrisetoprominenceanditsrecognitionasthemostfrequentlyalteredgeneinhumancancerwasratherlongandwinding,withconceptsbeingrepeatedlyrevised,extensivelymodifiedandsometimeseventotallyturnedupsidedown.Thehistoryofp53researchoverthelast30yearsprovidesarichexampleofhowknowledgeevolvesinunexpectedwaysandhowbothresearch“fashions”andnewmethodologicalbreakthroughsmakeusperceivethesamefactsintotallydifferentwaysastimeprogresses.Italsoteachesushowextensivedelvingintoasingleproteincanleadtothediscoveryofnewfundamentalandgeneralprinciplesthatapplytomuchbroaderareasofbiologyandbiochemistry.
Prelude:
tumorviruses,oncogenesandtheroadtop53
Inthe1970’s,muchoftheattentionof“modern”cancerresearchersfocusedoncancer-causingviruses.Inparticular,itbecameevidentthatsuchvirusescarriedoncogenes.ThebiggerpicturewasfirstresolvedforRNAtumorviruses;
there,itwasshownthatthevirus“hijacks”acellulargene,whichitsubsequentlyreintroducesintothecellthatitinfects2.Thisleadstothevastoverexpressionoftheencodedcellularprotein,sometimesinmodifiedform,andeventuallycausestransformation.Similarly,oncogeneswereuncoveredbyexaminingthegenesadjacenttotheintegrationsitesofretrovirusesthatresultedintheoverexpressionofthosegenesandtheformationoftumorsinanimals.
Overthenextfifteenyearsalonglistofoncogeneswereidentifiedanditbecameclearthatoncogeneswerethecauseofcancersinanimals.Itwasthusnotatallfar-fetchedtoexpectthatDNAtumorvirusesmightoperatebyessentiallythesameprinciple–thattheyhadpickeduponcogenesfromthecellorencodedtheirownviraloncogenes.ItbecamerapidlyclearthattheDNAtumorvirusescontainedoncogenesnotrelatedtothecellularoncogenesoftheRNAtumorviruses.Buthowdidtheseviraloncogenesacttotransformcellsandproducetumorsinanimals?
ItwasproposedthattheDNAtumorvirusoncogenesencodeviralproteinsthatleadindirectlytotheexcessiveinductionofputativecellularoncoproteins.Itwasonthatfertileconceptualsoilthatp53firstemerged.
TumorsinducedinexperimentalanimalsbysmallDNAtumorviruses,suchasSV40,typicallyexpressalimitednumberofviralencodedproteins.Thesearerecognizedbytheimmunesystemofthehost,leadingtotheproductionofantibodiesagainsttheseproteins.Bythemid-1970’s,suchantibodiesstartedtogainpopularityastoolstoidentifyandmonitorproteinsencodedbytheviralgenomeandexpressedintransformedcells.Basedontheirmodeofdetection,theseproteinsweredubbedviraltumorantigens.Subsequentgeneticanalysisrevealedthatthegenesencodingtheseviraltumorantigenswereoftenthosealsoresponsibleforthetransformingactivityofthevirus,namelytheviraloncoproteins.InthecaseofSV40,thetwoviralproteinsidentifiedinthismannerwerecalledlargeT-antigenandsmallt-antigen,respectively.
ItwaswhilestudyingtheseSV40-derivedtumorantigensthatseveralgroupsindependentlystumbledonp53.Thishappenedin1979,thirtyyearsago(Timeline).WorkingattheICRF(nowLondonInstituteforCancerResearch),DavidLaneandLionelCrawfordrealizedthatwhenserafromanimalsbearingSV40-inducedtumorswereemployedtoimmunoprecipitateSV40largeT-antigen,anon-viralproteinwithanapparentmolecularmassofabout53kDacamealongfortheride3.FurtheranalysisestablishedthatthiscellularproteinwasphysicallycomplexedwithSV40largeT-antigen.Thustheviralprotein,previouslyshowntobelargelyresponsibleforthetransformingandtumorigenicactivityoftheSV40virus,hadselectedthishithertounknowncellularproteinasitspartnerforanintimate,specificinteraction.Atthesametime,DanielLinzerandArnoldLevineappliedasimilarimmunologicalapproachtoSV40transformedcells,andcameupwithessentiallythesameobservations,namelythatsuchcellsharboredacomplexbetweentheSV40largeT-antigenandthecellular53kDaprotein4.Threeothergroups,thoseofAlanSmithintheUK,RobertCarrollinNewYorkandPierreMayinFrance,simultaneouslymadeverysimilarfindings,allpublishedin19795-7.
Interestingly,LinzerandLevinealsofoundthattheirantiseraprecipitatedthesame53kDaproteinfromteratocarcinoma(agermcelltumor)-derivedcells,despitethefactthatthelatterdidnotharboranySV40proteins;
thisindicatedthatasubsetoftheantibodiesraisedagainsttheviral-inducedtumorwerecapableofinteractingdirectlywiththiscellularprotein4.Inparallel,LloydOldandcoworkersdemonstratedthatanimalsimmunizedwithnon-virallytransformedcellsproducedantibodiestothesame53kDaprotein8,rightfullyqualifyingitasacellulartumorantigen.Moreover,VardaRotter,workinginthelabofDavidBaltimore,wasabletoidentifythesameproteinbeingproducedinexcessincellstransformedbyaretrovirus,theAbelsonmurineleukemiavirus9.Hence,veryhighlevelsofthisnewcellularproteinwerepresentnotonlyinSV40-transformedcellsbutalsoinothertypesofcancercells,butlittleornop53proteincouldbedetectedinnon-transformedcells.
Asisoftenthecasewithindependentdiscoveriesofthesameprotein,eachlabgaveitadifferentnameandcontinuedtopublishsubsequentpapersusingtheirfavoritename,creatingquiteabitofconfusioninthisveryyoungfield.Itwasonlyin1983,duringthefirstp53WorkshopinOxted,UK(Fig.1),thatrepresentativesofthedifferentp53groupsgottogethertodiscussacommonnomenclature.Afterareasonabledealofinevitabledebate,theterm“p53”emergedasthewinnerandhasstayedwithuseversince.Ironically,p53isactuallyamisnomer.Whencoined,itpurportedlyrelatedtothemolecularmassoftheprotein,whichonthebasisofitsmigrationinSDS-polyacrylamidegelswasestimatedtobeabout53kDa.Asrealizedlater,thiswasagrossoverestimate,presumablyduetothepresenceofaproline-richregionthatslowsdownthemigrationoftheproteininsuchgels.Infact,thecorrectmolecularmassofthehumanp53proteinisonly43.7kDa,andthatofthemouseproteinisevenless.Butwhowoulddarechangeawinningname?
Fig.1
Thefirstp53workshop
Fig.1
Thefirstp53workshoptookplaceatTheMarieCurieResearchInstituteatTheChartinOxted,Surrey,UKfrom7-10May1983.Theprogramdidnotincludeanypresentationtitles,butthehottestissuedontheagendawerethefirstdisclosuresoftheclonedmurinep53cD