The first 30 years of p53.docx

The first 30 years of p53.docx

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Thefirst30yearsofp53

Thefirst30yearsofp53:

growingevermorecomplex

ArnoldJ.Levine1andMosheOren2

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.

∙ OtherSections▼

oAbstract

oPrelude:

tumorviruses,

oncogenesandtheroadtop53

oTheearlyyears:

p53isanoncogene?

oGrandentryintothetumorsuppressormainstage

oHowdoesp53doit?

op53andMDM2:

inandoutofloops

oWhatisthisgoodfor?

p53andcancertherapy

oRestoringp53activity

oTheFuture

oReferences

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.

∙ OtherSections▼

oAbstract

oPrelude:

tumorviruses,

oncogenesandtheroadtop53

oTheearlyyears:

p53isanoncogene?

oGrandentryintothetumorsuppressormainstage

oHowdoesp53doit?

op53andMDM2:

inandoutofloops

oWhatisthisgoodfor?

p53andcancertherapy

oRestoringp53activity

oTheFuture

oReferences

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

Thefirstp53workshop

Thefirstp53workshoptookplaceatTheMarieCurieResearchInstituteatTheChartinOxted,Surrey,UKfrom7-10May1983.Theprogramdidnotincludeanypresentationtitles,butthehottestissuedontheagendawerethefirstdisclosuresoftheclonedmurinep53cD