细胞凋亡(12级英文班)1127.ppt

CellularAgingandApoptosis Chapter10 Senescence oraging andapoptosis orprogrammedcelldeath PCD aretwocommoncellfates Whileapoptosisleadstodeathandremovalofthecells senescencecellspersistandsurviveforextendedperiodsoftime unabletomaintaintheirnormalfunctions Bothsenescenceandapoptosisareimportantfordevelopment Section1CellularAging cellsenescence Cellularagingnamelysenescence isdefinedasprogressivedeteriorationinphysiologicalfunctionsandmetabolicprocessesofacellororganism Itistheuniversal graduallyirreversiblechangesinstructureandfunctionofacell Almostalllivingorganismspassthroughasequenceofchanges characterizedbygrowth development maturationandsenescence Normalhumansomaticcellslosetheirdividingpotentialandbecomesenescentafterabout50to60divisions TheHayflicklimit Hayflicklimitationisthenumberoftimesacellwilldividebeforeitstopsduetothetelomerereachingacriticallength TheHayflicklimitwasdiscoveredbyLeonardHayflickin1961 whenHayflickdemonstratedthatapopulationofnormalhumanfetalcellsinacellculturedividebetween40and60times Itthenentersasenescencephase refutingthecontentionthatnormalcellsareimmortal Inbiology senescenceisthestateorprocessofaging Cellularsenescenceisaphenomenonwhereisolatedcellsdemonstratealimitedabilitytodivideinaculturedish whileorganismalsenescenceistheagingoforganisms Youngcellsafter20populationdoublings PDs Oldercellsenteringasenescentphaseafter50populationdoublings TheHayflickLimit Thelifespanofcellsislimited Thepotentialofcellproliferationwouldlosegraduallyfollowingvigorouscelldivision eventuallyleadingtothesenescenceanddeathofcells Somecancerandvirus infectedcellsarenotrestricted seeminglywithaninfinitedoublingpotential andarethus immortal celllines Thelifetimeofcellsculturedinvitrodependsonthenumbersofserialsubcultivation ratherthanthedaysofculture Thenumberofsubculturingcellsinvitropositivelycorrelateswiththelifespanofthedonorspecies Thenumberofsubculturingcellsinvitroculturednegativelycorrelateswiththeageofdonor Lifespanofcellsinvitroculture Characteristicsofcellaging Slowdownofcellproliferation Decreaseinnumberandincreaseinsizeofmito chondrion mitochondrialoxidativephosphory lationisreduced asissynthesisofstructural enzymaticandreceptorproteins Increaseinresidualbodiesassociatedwithagepigments Decreaseincellsizeassociatedwithincreaseinnucleus cytoplasmratio DisperseddistributionofrER distortedGolgiapparatuses Invaginationofnuclearmembraneandpyknosisofchromatin Alteredgeneexpression celljunctiondecreaseandfluidityofmembranedecline Theoryofsenescence Geneticcontroltheoryaging associatedgene WRN Sirtuins Bcl 2etal FreeradicaltheoryTelomeretheoryAccumulationofmetabolicwastestheoryCumulativedamagetheorymtDNAmutationtheory Geneticcontroltheory Hutchinson Gilfordsyndrome Werner sSyndrome Amutantmodelmouseisusefulforstudiesofaging Theklothophenotype prematureaging iscausedbyadisruptionofthesinglegene klotho Freeradicaltheory Freeradicalsorreactiveoxygenspecies ROS canbeformedbydifferentprocessesincludingnormalcellmetabolicprocesses Theyaresuchhighlyreactivemoleculesthattheycandamageallsortsofcellularcomponents especiallybiomacromolecules Cellscontinuouslyproducefreeradicals andconstantradicaldamageeventuallykillsthecell Mitochondria regionsofthecellthatmanufacturechemicalenergy producefreeradicalsandaretheprimarysitesforfreeradicaldamage TheprimarysiteofradicaloxygendamageismitochondrialDNA mtDNA Generally harmfuleffectsofROSsonthecellincludedamageofDNA oxidationsofpolydesaturatedfattyacidsinlipids oxidationsofaminoacidsinproteins oxidativelyinactivatespecificenzymesbyoxidationofco factors Telomeretheory Telomeres theregionsattheendsofchromosomes becomeshorterwitheachcelldivision Fortunately oncethetelomeresarereducedtoacriticalminimumsize thep53genenotesthisandcausesthecelltostopreplicatingandtodie Ithaslongbeenappreciatedthattelomeres therepetitiveDNAthatcapstheendsoflinearchromosomes areessentialstructuresthatpreventchromosomefusionandgenomicinstability Intheabsenceoftheenzymetelomerase whichcanaddtelomericrepeatsdirectlytotelomeres eachroundofDNAreplicationleavesunreplicated50 200bpof3 telomericDNA stop Thelengthoftelomeres Accumulationofmetabolicwastestheory Lipofuscinismembrane boundcellularwastethatcanbeneitherdegradednorejectedfromthecellbutcanonlybedilutedthroughcelldivision Accumulatingoflipofuscinhasbeenconsideredareliablebiomarkerfortheageofcellssuchasneurons Theaccumulationofgeneticchangessuchaspointmutations lossofchromosomesorchromosomalrearrangementsarethoughttobecausesofaging Inaddition errorsduringgenetranscriptionandtranslationcanproducewrongandvoidproteinandfinallyresultinmetabolicdisorderandcellaging Cumulativedamage errortheory Thereisaninvariantrelationshipbetweenlifespanandthenumberofrandommutations Anumberofstudiesatanumberofgenelocihaveshownthatsomaticmutationsofavarietyoftypesaccumulatewithage DeficientinDNARepairandTranscriptioninducePrematureAginginMice TTDandXPD genesforDNArepairandreplication SCIENCEVOL29617MAY2002 Photographofa3 week oldXPA TTDdouble mutant left TTD middle andXPA right mouse mtDNAmutationtheory Thehumanmitochondrioncarrytheinformationfor37geneswhichencode 2differentmoleculesofrRNA22differentmoleculesoftRNA13polypeptides MutationsinmitochondrialDNA mtDNA accumulationandconsequentmitochodrialdysfunctionintissuesofmammalianspecieshavebeenhypothesizedtocontributetoaging 二 复制性细胞衰老和氧化应激诱导的非端粒依赖性细胞衰老的调控 目前认为 主要有两条途径调控细胞的衰老 复制性细胞衰老依赖于p53 p21 pRb E2F信号通路的调控 氧化应激诱导的非端粒依赖性细胞衰老受ERK p38MAPK p16 pRb信号通路的调控 未能通过G1 S检查点的细胞将退出细胞周期 并走向衰老 CellSenescenceandCellDeath Deathisanuniversalphenomenaandistheirreversiblecessationoflifephenomena Therearetwowaysinwhichcellsdie theyarekilledbyinjuriousagents necrosis orinducedtocommitsuicide apoptosis Section CellDeath Cellnecrosis Cellnecrosisispassivecelldeathandiscausedbyexternalfactors suchasinfection toxins ortrauma Cytologicalcharacteristicsofnecrosis cellswellsmitochondrialdilatelossofmembraneintegrityDNAdegradationatrandomorganellesdissolveandtheplasmamembranerupturesreleasingcytoplasmicmaterialelicitsaninflammatoryresponsenoATPneeded ApoptosisNecrosis Apoptosisisainitiative suicide program Butthemechanismofnecrosisisnotclear andusually isconsidereda murder program Conceptofapoptosis Apoptosisisatypeoforderly orprogrammed celldeathinwhichthecellrespondstocertainsignalsbyinitiatinganormalresponsethatleadstothecelldeath Itisageneticallyregulatedcell suicide process markedbythebreakdownofmostcellcomponentsandaseriesofwell definedmorphologicalchanges Deathbyapoptosisisaneat orderlyprocess Morphologicchangesduringapoptosis Theoverallshrinkageinvolumeofthecellanditsnucleus Thelossofadhesiontoneighboringcells Theformationofblebsatthecellsurfaceandapoptoticbodies Thedissectionofthechromatinintosmallfragments Therapidengulfmentofthe corpse byphagocytosis Earlyinapoptosis chromosomecondensationoccursalongthenuclearperipheryandthecellbodyalsoshrinks Laterboththenucleusandcytoplasmfragment formingapoptoticbodies whicharephagocytosedbysurroundingcells Apoptoticbodiescontainstructurallyintactorganellesandchromaticfragments Noinflammationoccursinapoptoticcells Acomparisonofnormalandapoptoticcells Biochemicalchangeofapoptosis downregulationofBcl 2proteinsactivationofcaspasescleavageoftheDNArepairenzymePARPthereleaseofcytochromeCfrommitochondriathetranslocationofphosphatidylserine 磷脂酰丝氨酸 fromtheinnerendogenousendonuclease 核内切酶 releasepromotingDNAdegradationATPisneeded DNAladder Theactivationofspecificendonucleaseleadstodissectionofchromatininto180 200bpDNAladderalongtheconsecutivenucleosomes Biologicalsignificanceofapoptosis Apoptosisisimportantinmaintaininghomeostasisinmulticellularorganismsandfailuretoregulateapoptosiscanresultinseriousdamagetotheorganism HistogenesisduringindividualdevelopmentTumorsurveillance eliminationofthecellsthathavesustainedirreparablegenomicdamage Functionoftheimmunesystem eliminationoftheTlymphocytesthatpossessreceptorscapableofbindingtightlytonormalcellswithinthebody InvolvementinneurodegenerativediseasessuchasAlzheimer sdisease Parkinson sdisease andHuntington sdisease Sculptingthedigitsinthedevelopingmousepawbyapoptosis Theroleofsurvivalfactorsandcelldeathinadjustingthenumberofdevelopingnervecellstotheamountoftargetcells Comparisonofcellnecrosisandapoptosis Incontrasttoapoptosis necroticcellsthatdieinresponsetotissuedamageswellandburst releasingtheirintracellularcontents whichcandamagesurroundingcellsandfrequentlycauseinflammation ApoptosisvsNecrosis Molecularmechanismsofapoptosis Apoptosiscanbedividedintotwophases Activationphase Thecellrespondsto deathsignals derivedfromexteriororinteriorofthecell thatcommitittoundergoingself destruction Executionphase Thedeathsentenceiscarriedoutbycaspases Twoprinciplepathways 1 Extrinsicpathway FasSignalingPathway 2 Intrinsicpathway Mitochondrialpathway Extrinsicpathwayofapoptosis receptor mediatedpathway Apoptoticsignals TheTumorNecrosisFactor TNF familycomprisesseveralligands suchastheprototypeTNFa theFasLigand FasL andTNF relatedapoptosis inducingligand TRAIL Apo2L TNFisproducedbyT cellsandactivatedmacrophagesinresponsetoinfection Apoptoticsignallingfromthedeathreceptors BindingofTNFatoitsreceptor TNFR1 resultsinreceptortrimerisationandclusteringofintracellulardeathdomains ThisallowsbindingoftwoadapterproteinsTRADDandFADD whichleadstotherecruitmentandcleavageofprocaspase 8 Activecaspase 8isaninitiatorcaspasethatactivatesdownstreamexecutionercaspases leadingtoapoptosis Intrinsicpathwayofapoptosis mitochondria mediatedpathway Deathsignals IrreparablegeneticdamageExtremelyhighofcytosolic Ca2 SevereoxidativestressAbsenceofgrowthfactors ActivationoftheintrinsicpathwayisregulatedbymembersoftheBcl 2familyofproteins StressfulstimuliactivatesproapoptoticmembersoftheBcl 2family suchasBax whichtheninserttheoutermitochondrialmembrane toincreasethepermeabilityofthemembraneandtopromotethereleaseofcertainmitochondrialprote