Download Cell Cycle Effects of Radiation

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Cell Cycle Effects of Radiation
CellCycle:Sequenceofchangesinacellstartingwiththemomentthecellis
createdbycelldivision,continuingthroughthedoublingoftheDNAandother
cellularcontents,andendingwithcelldivisioninto2daughtercells
Phasesofthecellcycle:
I.
Interphase(G1,S,andG2):thepartofthecellcyclethatexcludes
mitosis
G1:Gapbetweenpreviouscelldivision(M)andDNAreplication(S)
S:DNAreplication
G2:GapbetweenDNAreplication(S)andcelldivision(M)
II.
Mitosis(M):wherecopiedDNAandcytoplasmaredividedbetween
twodaughtercells
Cellscanexistinaquiescentstate(G0)wheretheyarenotinanactivecellcycle.
Thedecisiontoenterintoan
activecellcycledependson
extra-cellularsignalsand
nutrientslevelsthatsignalto
thenucleus.Acomplex
molecularcircuitry(“TheCell
CycleClock”)integratesallof
thesesignalstodecidewhether
toenterintoanactivecellcycle.
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David Kirsch, M.D., Ph.D., and Elaine Zeman, Ph.D.
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Cell Cycle Effects of Radiation
Mitosiscanbesubdividedintoprophase,metaphase,anaphase,andtelophase:
Prophase:Chromosomescondenseandbecome
visibleundermicroscope.Centrosomes
assembleatoppositepolesandbind
tomicrotubulesthatwillformthemitoticspindle.
Metaphase:Chromosomesaligninasymmetricalfashion
astheybecomeattachedatthemitotic
spindle.Nuclearmembranedisappears.
Anaphase:ThetwocopiesoftheDNAarepulled
intooppositedirections.
Telophase:Chromosomesde-condenseandanuclear
membraneformsaroundeachsetof
chromosomes.Thecellcompletesdivisioninto2daughtercells.
ProphaseMetaphaseAnaphaseTelophase
Blue=chromosomes
Green=microtubulefibersofthemitoticspindle
Centrosome:ismadeupof2centriolesthatareeachcomposedof9tripletsofmicrotubules
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Cell Cycle Effects of Radiation
TheCellCycleThroughtheAges
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Cell Cycle Effects of Radiation
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Cell Cycle Effects of Radiation
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Cell Cycle Effects of Radiation
CellCycleandDifferentiationofNormalTissueStemCells
Normaltissuestemcells
have2definingproperties:
(1)self-renewal
(2)differentiation
CellCycleandDifferentiationof“CancerStemCells”
ClonalEvolutionModelCancerStemCellModel
Cancerscanfollowthe
clonalevolutionmodelor
thecancerstemcellmodel
(ormaybeamixofthe
twomodels).Emerging
evidencesuggeststhat
cancerstemcellsmaybe
resistanttoradiation.
ReyaetalNature2001
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Cell Cycle Effects of Radiation
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Cell Cycle Effects of Radiation
InterphaseCell
MitoticCell
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Cell Cycle Effects of Radiation
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Cell Cycle Effects of Radiation
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Cell Cycle Effects of Radiation
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Cell Cycle Effects of Radiation
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Cell Cycle Effects of Radiation
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Cell Cycle Effects of Radiation
ZemanandBedfordRadiationRes101:373-393,1985
TheModern-DayCellCycle
Cellcyclecheckpoints:Control
mechanismstoensurethatthenext
stepinthecellcycledoesnotproceed
untilthespecificmoleculareventshave
occurredtocompletethecurrentphase
ofthecellcycle.Manyofthecellcycle
checkpointsarerelatedtothestatusof
DNA(DNAdamage)andcanbe
triggeredbyradiation.
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Cell Cycle Effects of Radiation
Tomovefromonephaseof
thecellcycletothenext,
proteinsarephosphorylated
byacomplexofacyclinanda
cyclin-dependentkinase
(CDK):
G1:CyclinD-CDK4orCDK6
CyclinE-CDK2
S:CyclinA-CDK2
CyclinA-CDC2
M:CyclinB-CDC2
Levelsof
cyclinschange
acrossthecell
cycle
Howdoesradiationcausecellcyclearrest?
CDKInhibitorsareup-regulatedbyradiationandactivatecellcyclecheckpoints.
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Cell Cycle Effects of Radiation
G1Checkpoint:
PreventsSphaseentryuntilafter
DSBisrepaired
RadiationactivatesATM
andCHK2proteinkinases
thatphosphorylatep53
proteinandincreasep53
proteinlevels.p53increases
p21levelsthatblock
cyclinE-cdk.
CDKsareregulatednotonlybythelevelsofcyclinsandCDKIs,butalsobythe
phosphorylationstatusoftheCDK.
G1Checkpoint:ForCDK2to
beactive,CDK2mustalsohavean
inhibitoryphosphateremovedbythe
Cdc25Aphosphatase.CHK2phosphorylates
Cdc25Aandtargetsitfordegradation.
WithoutCDC25A,CDK2retainsan
inactivatingphosphorylation.
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Cell Cycle Effects of Radiation
CDKsareregulatedbythephosphorylationstatusoftheCDKtocontrolentry
intomitosis.
PassagethroughmitosisrequireshighlevelsofcyclinBandactiveCdc2.
ForCdc2tobeactive,specificaminoacidsmustnothavephosphategroups.This
addsanotherlayerofregulationwithphosphatases(likeCdc25c)thatremove
phosphategroupstoactivateCdc2andkinases(likeWee1)thataddphosphate
groupstoinactivateCdc2.
ThephosphorylationofCDKscanchangeafterradiation,whichisanotherway
thatradiationcanaltercellcycleprogression.
Question:WhydomosttumorcellsnothaveaG1checkpointafterradiation?
Summary:
1) Cellcycleprogressiondependsontheactivityofcyclin-CDKcomplexes
a)Cyclinlevelschangeindifferentphasesofthecellcycle b)CDKsarealsoregulatedbyphosphorylation c)CDKI’sblockcyclin-CDKactivity
2) DNAdamageresponsetoradiationcanalterCDKactivitythroughthese
layersofregulation
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