OncogenesandTumorSuppressorGenes

SectionIOncogenes

Oncogenesaregeneswhoseproductshavetheabilitytotransformeukaryoticcellsincultureortoinducecancerinanimals,includingvirusoncogene（v-onc）andcellularoncogene(c-onc).Mostoncogenearemutantformsofnormalgenes

（proto-onc）involvedinthecontrolofcellgrowthordivision.V–oncogeneAnucleicacidsequenceinavirusresponsiblefortheoncogenicityofthevirus;itisderivedfromthecellularproto-oncogeneandacquiredfromthehostbyrecombination.

Retrovirallifecycle

Retroviraloncogenes(partiallist)V-oncPrototyperetrovirus

srcRoussarcomavirusmycAvianmyelocytomatosisviruserbA,erbBAvianerythroblastosisvirusmybAvianmyeloblastosisvirusH-rasHarveyratsarcomavirusK-rasKirstenmurinesarcomavirusablAbelsonmurineleukemiavirusfesFelinesarcomavirussisSimiansarcomavirusPro-oncogeneAnormalgenethathasthepotentialtobecomeanoncogene.

Cellularoncogeneaproto-oncogenethathasbeenactivatedwithinthehostsothatoncogenicityresults.

Characteristics–Theydistributewidelyfromyeasttohumanbeings;–Theyhavebeenhighlyconservedovereonsofevolutionarytime;–Lowexpressionlevel,basictoanimallife,theirproductsparticipateincellulargrowth-controllingpathways;–Wheninappropriatelyactivated,thesegenescanleadtoafaultingrowthcontrolandcontributetothedevelopmentofcancer.Productsandfunctionsofpro-oncogenes

–Growthfactors–Transmembranereceptorforgrowthfactors–Intracellularsignaltransducer:intracellulartyrosinekinases,Ser/Thrkinases,etc.–Transcriptionfactors

C-Erb-BC-ras,raf,srcC-mycC-sisC-erb-AMechanismofproto-oncogeneactivation–Promoterinsertionandenhancerinsertion–Chromosomal(gene)translocation(染色體易位)

andrearrangement–Geneamplification–Pointmutations

Promoter/enhancerinsertion

Whenretrovirusgenomeintegrateintocellchromosome,thestrongpromoter/enhancerintheretrovirusLTR(longterminalrepeat)canactivatesomeproto-oncogeneandinduceitsoverexpression.

ChromosometranslocationChromosomedistortion,breakortranslocationoftenoccurintumorcells.Chromosometranslocationisthatonepartofonechromosomeexchangewithanotherchromosome.Chromosometranslocationcancausechangesingenestructureandgeneexpression.Proto-oncogenecanbeactivatedandoverexpressedifitisclosetoastrongpromoter/enhancer.Burkitt'slymphoma(Burkitt's淋巴瘤)isasolidtumorofBlymphocytesItinvolvesareciprocaltranslocation(相互易位)thathasmovedtheproto-oncogenec-mycfromitsnormalpositiononchromosome8toalocationclosetotheenhancersoftheantibodyheavychaingenesonchromosome14.Thisleadstooverexpressionofthemyctranscriptionfactor.GeneamplificationProto-oncogenesbelongtosingle-copygenes.Proto-oncogenescanbeamplifiedinto50–500copies,anditsexpressionlevelcanbeincreasedby50—500fold.

PointmutationSinglebasechangeonecodechangedoneAAchangedactivitychange

Mutantproteincancontinuouslytransducegrowthsignalandcausecelltransformation.NormalH-rasGGCGTCCancerH-rasGly

Val

Proteins

encodedbyoncogenesNewproteinsSuperfluousnormalproteinsAbnormalproteins：devoidofimportantregulatoryelementsSectionIITumorSuppressorGenesTumorsuppressorgenesaregenesthathaveanegative,suppressingeffectontumorcreationandthushelptopreventformationoftumors.

Theretinoblastoma(視網(wǎng)膜母細(xì)胞瘤)genewasthefirsttumorsuppressorgenetobeidentifiedandcharacterizedinman.Inactivationoftheretinoblastomagenebymutationordeletionleadstocompletefailureofthefunctionofthegeneandthustotumorformation.

Rbhas2forms:

phosphorylatedRbprotein(inactiveform)

unphosphorylatedRbprotein(activeform)Function:controlcellcycleTheRbgeneproduct(RB,non-phosphorylated)interactswithaproteincalledE2F(transcriptionfactor).ThemutantRBisalwaysphosphorylatedandcannotregulateE2F,andnormalcellsbecomecancerous.

RBhasbeenshowntobeanegative

regulatorofprogressioninthecellcycle

attheG1toStransition:1.InG0/G1,unphosphorylatedRBbindstoatranscriptionfactor(E2F),whichinactivatesE2F.2.AttheendofG1,RBisphosphorylated,releasingE2F.3.ActiveE2FstimulatestheexpressionofgenesrequiredfortheentryintoS-phase(DNAreplication).4.Attheendofmitosis,RBisdephosphorylated,whichrendersitactive.Thep53protein

isanuclearphosphoproteinof393aminoacids,whichhavethreedomains.N-terminus(1-80)transcriptionalactivationdomain.Coresection(102-290)whichbindstoDNAinasequencespecificmanner.C-terminus(319-393)involvedintheoligomerizationoftheprotein.Functionsofp53protein:

––

Thep53proteincanprotecttheintegrityoftheDNA.InthepresenceofDNAdamage,thep53proteincanbringaboutahaltinthecellcycleattheG1/Stransition,andpromoteDNArepairassociatedgeneexpress.––

Thep53proteinfunctions