22 an introduction to genetic analysis.docx
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22 an introduction to genetic analysis.docx
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22anintroductiontogeneticanalysis
Chapter22
CancerasaGeneticDisease
KeyConcepts
Normalcellproliferationismodulatedbycellcycleregulation.
Apoptosisisanormalself-destructionmechanismthateliminatesdamagedandpotentiallyharmfulcells.
Signalingsystemspermitproliferationandapoptosistobecoordinatedwithinapopulationofcells.
Incancer,cellsproliferateoutofcontrolandavoidfail-safedestructionmechanismsthroughtheaccumulationofaseriesofspecialmutationsinthesamesomaticcell.
Manyoftheclassesofgenesthataremutatedtocausecancersareimportantcomponentsofthecellthatdirectlyorindirectlycontributetogrowthcontrolanddifferentiation.
Introduction
InChapter11,welearnedaboutsomewaysinwhichacellmonitorsitsstatusrelativetoitsenvironmentandrespondsaccordingly.Forexample,byutilizingcertainmetabolitesasallostericeffectorsoftranscriptionalregulatoryproteins,anE.colicellcanmakedecisionsaboutwhichsugarmetabolicpathwaystoimplementatanygiventime.Metazoa(multitissuedanimals)usesteroidsandotherlow-molecular-weighthormonesasallostericeffectorsoftranscriptionalregulatorymoleculestocoordinateappropriateresponsesofdifferentorganstoaparticularphysiologicalevent.
Amajorpointtorememberisthatcellshaveevolvedmechanismsthatmodulatetheactivityofkeytargetproteinsbyrelativelyminormodifications—inthetwoprecedingexamples,byformingcomplexeswithallostericeffectors.Muchofgenetics,indeedmuchofthebiologyofacell,dependsonsuchmodulations,inwhichkeyproteinsaretoggledbetweenactiveandinactivestates.
Inthischapterandthenextone,weshallseethisthemeexploitedinavarietyofsituations:
controlofcellnumbers,controlofdevelopmentalpathways,andformationofcomplexbiologicalpatterns.Inthischapter,wefocusonhowsuchmodulationsachievepropercontrolofcellnumberandhowthesystemscanbeovercomebycertainclassesofmutationstoproduceuncontrolledproliferation—thediseasesthatwecallcancers.
Cancerandthecontrolofcellnumber:
anoverview
Cancerisnowclearlyunderstoodasageneticdiseaseofsomaticcells.Incancer,thefail-safemechanismsthatareinplacetoensurethatcellnumberremainsbalancedtotheneedsofthewholeorganismaresubverted,andcancerouscellsproliferateoutofcontrol.Tounderstandhowcellscanmutatetoacancerousstate,wemustfirstunderstandthebasicmechanismsgoverningthecontrolofnormalcellnumbers.
Machineryofcellproliferation
Certainaspectsofproliferationcontrolaregeneraltoallorganisms.Universally,thecelldivisionprocesshasnumerouseventsthatmusttakeplacesequentiallytoproduceviableprogenycells.Moreover,thecelldivisioncyclehasevolvedsothattherearechecksandbalancestopreventasubsequenteventfromtakingplacebeforetheprerequisiteeventshavebeenachieved.Forexample,itwouldbealethaleventifmitosisoccurredbeforeDNAreplicationwascompleted.Mechanismshaveevolvedthatpreventsuchcellulardisasters.Weshallexploretheregulationoftheeukaryoticcellcycle.Proteinkinases,enzymesthatspecificallyphosphorylatecertainaminoacidresiduesontargetproteins,andproteinphosphatases,enzymesthatspecificallyremovephosphategroupsfromsuchaminoacidresidues,modulatetheactivitiesofkeyproteinsinthecelldivisioncycle.Thesephosphorylation–dephosphorylationpathwaysultimatelyconvergetodeterminewhichkeyproteinsareactiveforafractionoftheentirecelldivisioncycle.Putanotherway,itisthecyclicalvariationsinthesekeyproteinsthatdeterminewhichpartsofthecellcyclearecurrentlybeingexecuted.
Machineryofcelldeath
Someaspectsofcellcontrolappeartohaveevolvedonlyinmulticellularorganisms.Todevelopandmaintainthemselvesnormally,multicellularorganismsmustproperlybalancethenumbersofthecelltypesintheirvarioustissues.Almostallofthesecelltypesaresomatic—thatis,theydonotcontributetothegermline.Lossofsuchsomaticcellsisnotaproblemfortheorganismfromthepointofviewofpropagationofthespecies,aslongasproliferationoftheremainingcellsofthattypeinaparticulartissuecompensatesforthecellsthatareeliminated.Furthermore,abnormalcellshavethepotentialtodoconsiderableharm.Thus,mechanismshaveevolvedtoeliminatecertaincells—throughaprocesscalledprogrammedcelldeathorapoptosis.Acascadeofenzymescalledcaspaseskillbydisruptingnumerousstructuralandfunctionalsystemswithinthecell.Subsequently,thecarcassesofthedeadcellsareremovedbyscavengercells.
Linkingcellproliferationanddeathtotheenvironment
Thecellproliferationandcelldeathmachinerymustbeinterconnectedsothateachisactivatedonlyundertheappropriateenvironmentalcircumstances.Forexample,inadultorgans,maintenanceofpropercellnumberrequiresproperbalancebetweenthebirthofnewcellsandthelossofexistingones.Eukaryoticcellshaveevolvedelaborateintercellularsignalingpathwaystoserveasstatusindicatorsoftheenvironment.Somesignalsstimulateproliferation,whereasothersinhibitit.Furthermore,othersignalscanactivateapoptosis,whereasstillothersblockactivation.Intercellularsignalingpathwaystypicallyconsistofseveralcomponents:
thesignalsthemselves,thereceptorsthatreceivethesignals,andthesignaltransductionsystemsresponsibleforrelayingthesignaltovariousregionsofthecell.JustasallostericeffectorsregulatetheactivityofmanyDNA-bindingproteinsinbacteria,modificationstothevariouscomponentsoftheintercellularsignalingsystems—proteinphosphorylation,allostericinteractionsbetweenproteinsandsmallmolecules,orinteractionbetweenproteinsubunits—controltheactivityofthesepathways.
Cellproliferationmachinery
Cellcycle
Therearefourmainpartstothecellcycle:
Mphase—mitosis—andthethreepartsthatarecomponentsofinterphase;G1,thegapperiodbetweentheendofmitosisandthestartofDNAreplication;S,theperiodduringwhichDNAsynthesisoccurs;andG2,thegapperiodfollowingDNAreplicationandprecedingtheinitiationofthemitoticprophase.Inmammals,wherethecellcycleisparticularlywellstudied,differencesintherateofcelldivisionarelargelyduetodifferencesinthelengthoftimebetweenenteringandexitingG1.ThisvariationisduetoanoptionalG0restingphaseintowhichG1-phasecellscanshuntandremainforvariablelengthsoftime,dependingonthecelltypeandonenvironmentalconditions.Conversely,S,G2,andMphasesarenormallyquitefixedinduration.Inthissection,weconsiderthemoleculesthatdrivethecellcycle.Inalatersection,weshallconsiderhowthesemoleculesareintegratedintotheoverallbiologyofthecell.
Cyclinsandcyclin-dependentproteinkinases
Theenginesthatdriveprogressionfromonestepofthecellcycletothenextareaseriesofproteincomplexescomposedoftwosubunits:
acyclinandacyclin-dependentproteinkinase(abbreviatedCDK).Ineveryeukaryote,thereisafamilyofstructurallyandfunctionallyrelatedcyclinproteins.Cyclinsaresonamedbecauseeachisfoundonlyduringoneoranothersegmentofthecellcycle.Theonsetoftheappearanceofaspecificcyclinisduetocell-cycle-controlledtranscription,inwhichthepreviouslyactivecyclin–CDKcomplexleadstotheactivationofatranscriptionfactorthatactivatesthetranscriptionofthisnewcyclin.Thedisappearanceofacyclindependsonthreeevents:
rapidinactivationoftheactivatoroftranscriptionofthiscyclin'sgene(sothatnonewmRNAisproduced),ahighdegreeofinstabilityofthecyclinmRNA(sothattheexistingpoolofmRNAiseliminated),andahighlevelofinstabilityofthecyclinitself(sothatthepoolofcyclinproteinisdestroyed).
Cyclin-dependentproteinkinasesalsoconstituteafamilyofstructurallyandfunctionallyrelatedproteins.Kinasesareenzymesthataddphosphategroupstotargetsubstrates;forproteinkinasessuchasCDKs,thesubstratesareproteins.CDKsaresonamedbecausetheiractivitiesareregulatedbycyclinsandbecausetheycatalyzethephosphorylationofspecificserineandthreonineresiduesofspecifictargetproteins.
ThetargetproteinsforCDKphosphorylationaredeterminedbytheassociatedcyclin.Inotherwords,thecyclintethersthetargetproteinsothattheCDKcanphosphorylateit(Figure22-1),therebychangingtheactivityofeachtargetprotein.Becausedifferentcyclinsarepresentatdifferentphasesofthecellcycle(Figure22-2),differentphasesofthecellcyclearecharacterizedbythephosphorylationofdifferenttargetproteins.Thephosphorylationeventsaretransientandreversible.Whenthecyclin–CDKcomplexdisappears,thephosphorylatedsubstrateproteinsarerapidlydephosphorylatedbyproteinphosphatases.
CDKtargets
Howdoesthephosphorylationofsometargetproteinscontrolthecellcycle?
Phosphorylationinitiatesachainofeventsthatculminatesintheactivationofcertaintranscriptionfactors.Thesetranscriptionfactorspromotethetranscriptionofcertaingeneswhoseproductsarerequiredforthenextstageofthecellcycle.Muchofourknowledgeofthecellcyclecomesfrombothgeneticstudiesinyeast(seenextsection)andfrombiochemicalstudiesofculturedmammaliancells.Awell-understoodexampleistheRb–E2Fpathwayinmammaliancells.RbisthetargetproteinofaCDK–cyclincomplexcalledCdk2–cyclinA,andE2FisthetranscriptionfactorthatRbregulates(Figure22-3).FromlateMphasethroughthemiddleofG1,theRbandE2Fproteinsarecombinedinaproteincomplexthatisinactive
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