Post on 07-Apr-2018
8/6/2019 Biology Review Part 3
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BiologyReviewpart3(bysomewikimaterial,EssentialCellBiology,andpersonaladds)
(Maytheforcebewithus)
Cellularsenescenceandmedicalimplication
Cellularsenescenceisthephenomenonbywhichnormal
diploidcellslosetheabilitytodivide,normallyafterabout
50celldivisionsinvitro.Somecellsbecomesenescentafter
fewerreplicationscyclesasaresultofDNAdoublestrandbreaks,toxins,etc.Thisphenomenonisalsoknownas
"replicativesenescence",the"Hayflickphenomenon",orthe
HayflicklimitinhonourofDr.LeonardHayflickwhowasthe
firsttopublishthisinformationin1965.InresponsetoDNA
damage(includingshortenedtelomeres),cellseitherageor
self-destruct(apoptosis,programmedcelldeath)ifthe
damagecannotbeeasilyrepaired.Inthis'cellularsuicide',
thedeathofonecell,ormore,maybenefittheorganismasawhole.Forexample,inplantsthedeathofthewater-
conductingxylemcells(tracheidsandvesselelements)
allowsthecellstofunctionmoreefficientlyandsodeliver
watertotheupperpartsofaplant.Theonesthatdonotself-
destructremainuntildestroyedbyoutsideforces.
Asnotedabove,senescenceisnotuniversal,andsenescence
isnotobservedinsingle-celledorganismsthatreproducethroughtheprocessofcellularmitosis.Moreover,cellular
senescenceisnotobservedinseveralorganisms,including
perennialplants,sponges,corals,andlobsters.Inthose
specieswherecellularsenescenceisobserved,cells
eventuallybecomepost-mitoticwhentheycannolonger
replicatethemselvesthroughtheprocessofcellularmitosis;
i.e.,cellsexperiencereplicativesenescence.Howandwhy
somecellsbecomepost-mitoticinsomespecieshasbeenthesubjectofmuchresearchandspeculation,but(asnoted
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above)itiswidelybelievedthatcellularsenescenceevolved
asawaytopreventtheonsetandspreadofcancer.Somatic
cellsthathavedividedmanytimeswillhaveaccumulated
DNAmutationsandwouldthereforebeindangerof
becomingcancerousifcelldivisioncontinued.
Lately,theroleoftelomeresincellularsenescencehas
arousedgeneralinterest,especiallywithaviewtothe
possiblegeneticallyadverseeffectsofcloning.The
successiveshorteningofthechromosomaltelomereswith
eachcellcycleisalsobelievedtolimitthenumberof
divisionsofthecell,thuscontributingtoaging.Therehave,
ontheotherhand,alsobeenreportsthatcloningcouldaltertheshorteningoftelomeres.Somecellsdonotageandare,
therefore,describedasbeing"biologicallyimmortal".Itis
theorizedbysomethatwhenitisdiscoveredexactlywhat
allowsthesecells,whetheritbetheresultoftelomere
lengtheningornot,todividewithoutlimitthatitwillbe
possibletogeneticallyalterothercellstohavethesame
capability.Itisfurthertheorizedthatitwilleventuallybe
possibletogeneticallyengineerallcellsinthehumanbodytohavethiscapabilitybyemployinggenetherapyand,
therefore,stoporreverseaging,effectivelymakingthe
entireorganismpotentiallyimmortal.
Thelengthofthetelomerestrandhassenescenceeffects,
telomereshorteningactivateextensivealterationsin
alternativeRNAsplicingthatproducesenescencetoxins
suchasprogerinthatdegradesthetissueandmakesitmore
susceptibletofailure.Cancercellsareusuallyimmortal.Inabout85%oftumors,
thisevasionofcellularsenescenceistheresultofup-
activationoftheirtelomerasegenes.Thissimpleobservation
suggeststhatreactivationoftelomeraseinhealthy
individualscouldgreatlyincreasetheircancerrisk.
Whethercellsenescenceplaysanyroleinorganismalaging
isatpresentunknown,andisanactiveareaofinvestigation.
Mousemutantslackingtelomerasedonotimmediatelyshowacceleratedaging.
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CellularDeath,NecrosisandApoptosis
Necrosisistheprematuredeathofcellsandlivingtissue.
Necrosisiscausedbyfactorsexternaltothecellortissue,
suchasinfection,toxins,ortrauma.Thisisincontrastto
apoptosis,whichisanaturallyoccurringcauseofcellular
death.Whileapoptosisoftenprovidesbeneficialeffectsto
theorganism,necrosisisalmostalwaysdetrimentalandcan
befatal.
Cellsthatdieduetonecrosisdonotusuallysendthesame
chemicalsignalstotheimmunesystemthatcellsundergoing
apoptosisdo.Thispreventsnearbyphagocytesfromlocatingandengulfingthedeadcells,leadingtoabuild-upofdead
tissueandcelldebrisatornearthesiteofthecelldeath.For
thisreason,itisoftennecessarytoremovenecrotictissue
surgically,aprocessknownasdebridement.
Causesofnecrosis:
Cellularnecrosiscanbeinducedbyanumberofexternalsources,includinginjury,infection,cancer,infarction,
poisons,ROS(ReactiveOxygenSpecies),andinflammation.
Forexample,aninfarction(blockageofbloodflowto
musculartissue)causesnecrosisofmuscletissueduetolack
ofoxygentotheaffectedcell,suchasoccursinamyocardial
infarction--aheartattack.Certainspider(brownrecluse)
andsnake(rattlesnake,Bothrops)venomscancause
necrosisofthetissuenearthebitewound,ascanaGroupAstreptococcusinfection(oneofthe"flesh-eating"bacteria).
Necrotictissuedoesnotundergothesamechemical
reactionsthatnormallydyingapoptotictissuedoes.The
suddenfailureofonepartofthecelltriggersacascadeof
events.Inadditiontothelackofchemicalsignalstothe
immunesystem,cellsundergoingnecrosiscanrelease
harmfulchemicalsintothesurroundingtissue.Inparticular,
cellscontainsmallorganellescalledlysosomes,whicharecapableofdigestingcellularmaterial.Damagetothe
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lysosomemembranecantriggerreleaseofthecontained
enzymes,destroyingotherpartsofthecell.Worse,when
theseenzymesarereleasedfromthenon-deadcell,theycan
triggerachainreactionoffurthercelldeath.Ifasufficient
amountofcontiguoustissuenecrotizes,itistermed
gangrene.Propercareandtreatmentofwoundsoranimal
bitesplaysakeyroleinpreventingthistypeofwidespread
necrosis.Duringasurgicalbiopsy,thisnecrosischain-
reactionishaltedbyfixationorfreezing.[citationneeded]
Necrosistypicallybeginswithcellswelling,chromatin
digestion,anddisruptionoftheplasmamembraneand
organellemembranes.LatenecrosisischaracterizedbyextensiveDNAhydrolysis,vacuolationoftheendoplasmic
reticulum,organellebreakdown,andcelllysis.Therelease
ofintracellularcontentafterplasmamembraneruptureis
thecauseofinflammationinnecrosis.
Apoptosis(keyfeatures)
Isaformofcellulardeathtriggeredbyactivationofdeathreceptors,withdrawalofsurvivalfactors,orasa
resultofDNAdamage
Apoptosisinvolvestheorderlydismantling(makinginpieces)ofadyingcellscontents
Proteasescalledcaspasesarekeymediatorsofapoptosis.Initiatorcaspasescanbeactivatedinseveral
ways,includingthroughthereleaseofcytochromec
frommitochondria.Initiatorcaspasesactivateexecutionercaspases,whichinturnactivateother
apoptosisproteins.
Stepbystepinductionofapoptosis:
1.Celldeathsignals,suchasligandsonthesurfaceofacytotoxicTlymphocyte,canleadtoapoptosis.
2.Ligandbindstoadeathreceptoronthesurfaceofatargetcell.Bindingcausesclusteringofreceptorsand
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recruitmentodadaptorproteinsinthetargetcell,
resultinginclusteringofinitiatorprocaspase-8protein
3.Initiatorcaspasesthenbecomeactivated4.Theinitiatorcaspasesinturnactivatetheexecutioner
caspase-3,akeyinitiatorofapoptosis
5.Whensurvivalfactorsarenolongerpresent6.Death-promotingproteinsaccumulate,
counterbalancinganti-apoptoticproteinsatthe
mitochondrialoutermembranecausingthereleaseof
cytochromec
7.Thislastformsacomplexwithotherproteins,resultinginactivationofaninitiatorcaspase-98.Theinitiatorcaspaseinturnactivatestheexecutionerscaspase-3,triggeringapoptosis
9.DNAdamagecanalsoleadtoapoptosisthroughtheactivityoftheproteinp53
Medicalimplication(thxwiki)
DefectiveapoptoticpathwaysThemanydifferenttypesofapoptoticpathwayscontaina
multitudeofdifferentbiochemicalcomponents,manyof
themnotyetunderstood.[34]Asapathwayismoreorless
sequentialinnature,itisavictimofcausality;removingor
modifyingonecomponentleadstoaneffectinanother.Ina
livingorganismthiscanhavedisastrouseffects,ofteninthe
formofdiseaseordisorder.Adiscussionofeverydisease
causedbymodificationofthevariousapoptoticpathwayswouldbeimpractical,buttheconceptoverlyingeachoneis
thesame:thenormalfunctioningofthepathwayhasbeen
disruptedinsuchawayastoimpairtheabilityofthecellto
undergonormalapoptosis.Thisresultsinacellthatlives
pastits"use-by-date"andisabletoreplicateandpasson
anyfaultymachinerytoitsprogeny,increasingthe
likelihoodofthecellbecomingcancerousordiseased.
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InhibitionofApoptosis
Inhibitionofapoptosiscanresultinanumberofcancers,
autoimmunediseases,inflammatorydiseases,andviral
infections.Itwasoriginallybelievedthattheassociated
accumulationofcellswasduetoanincreaseincellular
proliferation,butitisnowknownthatitisalsoduetoa
decreaseincelldeath.Themostcommonofthesediseasesis
cancer,thediseaseofexcessivecellularproliferation,which
isoftentimescharacterizedbyanoverexpressionofIAP
familymembers.Asaresult,themalignantcellsexperience
anabnormalresponsetoapoptosisinduction:cycle
regulatinggenes(suchasp53,rasorc-myc)aremutatedorinactivatedindiseasedcells,andfurthergenes(suchasbcl-
2)alsomodifytheirexpressionintumors.
HyperactiveApoptosis
Ontheotherhand,lossofcontrolofcelldeath(resultingin
excessapoptosis)canleadtoneurodegenerativediseases,
hematologicdiseases,andtissuedamage.Theprogressionof
HIVisdirectlylinkedtoexcess,unregulatedapoptosis.Inahealthyindividual,thenumberofCD4+lymphocytesisin
balancewiththecellsgeneratedbythebonemarrow;
however,inHIV-positivepatients,thisbalanceislostdueto
aninabilityofthebonemarrowtoregenerateCD4+cells.In
thecaseofHIV,CD4+lymphocytesdieatanacceleratedrate
throughuncontrolledapoptosis,
TheprogressionofthehumanimmunodeficiencyvirusinfectionintoAIDSisprimarilyduetothedepletionofCD4+
T-helperlymphocytesinamannerthatistoorapidforthe
body'sbonemarrowtoreplenishthecells,leadingtoa
compromisedimmunesystem.
Virusescantriggerapoptosisofinfectedcellsviaarangeof
mechanismsincluding:
Receptorbinding ActivationofproteinkinaseR(PKR)
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Interactionwithp53 ExpressionofviralproteinscoupledtoMHCproteins
onthesurfaceoftheinfectedcell,allowingrecognition
bycellsoftheimmunesystem(suchasNaturalKillerandcytotoxicTcells)thattheninducetheinfectedcell
toundergoapoptosis
KeypointsofthebiologyofCancer
Cancercellsproliferateinanuncontrolledwayandare
capableofspreadingbyinvasionandmetastasis Thebalancebetweencelldivisionanddifferentiationis
disruptedincancers,leadingtoaprogressiveincrease
inthenumberofdividingcells
Cancercellsareanchorage-independent,exhibitadecreasedsusceptibilitytodensity-dependent
inhibitionofgrowth,andarecapabletoreplenishtheir
telomeres
Sustainedtumorsgrowthrequiresanetworkofbloodvesselswhosegrowthistriggeredbyanincreased
productionofangiogenesisactivatorsandadecreased
productionofangiogenesisinhibitors
Cancercellsinvadesurroundingtissues,enterthecirculatorysystem,andmetastasizetodistantsites.
Invasionisfacilitatedbydecreasedcell-celladhesion,
increasedmotility,andsecretionofproteasesthat
degradetheextracellularmatrixandbasallamina.Onlyatinyfractionofthecancercellsthatenter
bloodstreamestablishsuccessfulmetastases
Sitesofmetastasesaredeterminedbythelocationofthefirstcapillarybedaswellasbyorgan-specific
conditionsthatinfluencecancercellgrowth
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Maincausesofcancer:
Somecancersarecausedbycertainkindsofchemicals,includingthosefoundintobaccosmoke.Chemicals
causecancerthroughamultistepprocessinvolving
initiation,promotion,andtumorprogression.Initiation
isbasedonDNAmutation,whereaspromotion
involvesaprolongedperiodofcellproliferation
accompaniedbyselectionofcellsexhibitingenhaced
growthproperties.Duringtumorprogression,
additionalmutationsaswellasepigeneticchangesin
geneexpressionproducecellswithincreasinglyaberranttraits
Cancercanalsobecausedbyionizingradiationandbysunlight,bothwhichtriggerDNAmutations,aswellas
bycertainviruses,bacteriaandparasites
Somecancer-causingvirusesactbydirectlytriggeringcellproliferation,eitherthroughtheactionofviral
genesorbyalteringthebehaviorofcellulargenes.
Othervirusesandinfectiousagentscreatetissuedestructionthatindirectlystimulatescellproliferation
underconditionsinwhichDNAdamageislikely
Oncogenesandtumorsuppressorgenes:
Oncogenesaregeneswhosepresencecancausecancer.Althoughoncogenesaresometimesbroughtintocells
byviruses,moreoftentheyarisefromnormalcellulargenes(proto-oncogenes)bypointmutation.Gene
amplification.Chromosomaltranslocation,localDNA
rearrangements,orinsertionalmutagenesis
Manyoftheproteinsproducedbyoncogenesaresignalingpathwaycomponents,suchasgrowthfactors,
receptors,plasmamembraneGTP-bindingproteins,
non-receptorsproteinkinases,transcriptionfactors,
andcellcycleorcelldeathregulators.Oncogenescode
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forabnormalformsorexcessivequantitiesofsuch
proteins,therebyleadingtoexcessivecellproliferation
Tumorsuppressorgenesaregeneswhoselossorinactivationcanleadtocancer.Susceptibilitytocancer
isincreasedinpeoplewhoinheritdefectivetumor
suppressorgenes
Thegeneticinstabilityofcancercellsfacilitatestheacquisitionofmultiplemutations