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THE CELL CYCLETHE CELL CYCLE
ItIt isis thethe periodperiod fromfrom thethe timetime aa cellcell
comescomes intointo existenceexistence untiluntil cellcell dividesdivides
intointo 22 daughterdaughter cellscells..
ItIt takestakes 2020 toto 2424 hourshours inin rapidlyrapidly
growinggrowing cellcell culturescultures..
InIn thethe humanhuman bodybody itit maymay bebe
fastfast asas inin cellcell cultureculture (hemopoietic(hemopoietic cells)cells)
maymay taketake 66--1212 monthsmonths (liver (liver cells)cells)..
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Phases of Cell CyclePhases of Cell Cycle
1.1. The gap 1 (G The gap 1 (G 11 ) phase ) phase
CellCell growthgrowth occurs.occurs.
It takesIt takes 99 hours in rapidly growinghours in rapidly growingcells.cells.
It may take several months(It may take several months(G0 phase).G0 phase).
2.2. The synthetic (S) phaseThe synthetic (S) phase DNA DNA synthesissynthesis occurs.occurs.
It takesIt takes 66--99 hours.hours.
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3 .3 . The gap 2 (G The gap 2 (G 22 )phase )phase
The cellThe cell preparesprepares itself for mitosisitself for mitosis It takesIt takes 44 hours.hours.
4 .4 . The mitotic (M) phaseThe mitotic (M) phase
CellCell divisiondivision occursoccurs It takesIt takes 11--22 hours.hours.
It includes nuclear division (It includes nuclear division ( k aryok inesisk aryok inesis ) )
followed by cytoplasmic division (followed by cytoplasmic division (cytok inesiscytok inesis ). ).
NB. TheNB. The GGll, S, and G, S, and G22 phases are called thephases are called the interphaseinterphase . .
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R EGULATION OF THE CELL CYCLER EGULATION OF THE CELL CYCLE
Cyclins (family of proteins) regulate the
transition of a cell from one phase to another.
The cyclins concentration increases anddecreases during different phases of the cell
cycle
The cyclins activate certain cyclin-
dependent protein kinases (CDK s) that phosphorylate substrates essential for the
passage of the cell from one phase to another.
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ItIt isis initiatedinitiated byby thethe bindingbinding of of aa growthgrowth factorfactor
toto itsits receptorreceptor onon thethe plasmaplasma membranemembrane of of thethe
cellcell..
TheThe growthgrowth factorfactor receptorreceptor undergoesundergoes autoauto--phosphorylationphosphorylation onon tyrosinetyrosine residuesresidues andand
becomesbecomes activeactive proteinprotein tyrosinetyrosine kinasekinase thatthat
cancan catalyzecatalyze phosphorylationphosphorylation of of certaincertain targettargetproteinsproteins onon tyrosinetyrosine residuesresidues..
AnAn intracellularintracellular signalsignal finallyfinally inducesinduces thethe
productionproduction of of cyclinscyclins..
Initiation of cell cycleInitiation of cell cycle
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During the G
During the Gll phase:phase: cyclincyclin
DDincreases lateincreases latein the Gin the Gll phasephase
It forms a complex with CDK 4 andIt forms a complex with CDK 4 and
CDK 6, calledCDK 6, called mitosis promoting factormitosis promoting factor
(MPF)(MPF)
MPF catalyzesMPF catalyzes phosphorylationphosphorylation of theof the
retinoblastoma (retinoblastoma (R bR b) protein.) protein.
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The R b protein is separated from transcriptionThe R b protein is separated from transcription
factorfactor E2FE2F required for the transcription of required for the transcription of
genes that code for proteins required to traversegenes that code for proteins required to traversethethe GGll--S restriction pointS restriction point, (point beyond which, (point beyond which
the cell continues to divide even in the absence of the cell continues to divide even in the absence of
the growth factor) which becomes active.the growth factor) which becomes active.
MPF can be inhibited by cyclin kinase inhibitoryMPF can be inhibited by cyclin kinase inhibitory
proteins (proteins (CIPCIP) (p16 & p21) which are also known) (p16 & p21) which are also known
as cyclin kinase inhibitor (CK I).as cyclin kinase inhibitor (CK I).
NB: TheNB: The dephosphorylateddephosphorylated R b protein binds to andR b protein binds to and
inactivatesinactivates E2FE2F
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In early S phase:In early S phase: TheThe EE andand AA cyclinscyclins
activate CDK activate CDK --2, which activates DNA 2, which activates DNA synthesis.synthesis.
During the S phaseDuring the S phase: cells contain large: cells contain large
quantities of enzymes required for DNA quantities of enzymes required for DNA synthesis.synthesis.
enzymes required for the synthesis of dNTPsenzymes required for the synthesis of dNTPs
thymidine kinasethymidine kinase dihydrofolate reductasedihydrofolate reductase
ribonucleotide reductaseribonucleotide reductase
DNA polymerasesDNA polymerases
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InIn GG22 phasephase :: BB cyclinscyclins areare producedproduced latelate inin thethe GG22
phasephase..
*They*They activateactivate CDK CDK --11,, aa proteinprotein kinasekinase
responsibleresponsible forfor traversingtraversing thethe GG22--MM checkpointcheckpoint..
*CDK *CDK --11 catalyzescatalyzes thethe phosphorylationphosphorylation of of::
((11)) HistonesHistones:: leadingleading toto condensationcondensation of of chromosomeschromosomes..
((22)) NuclearNuclear laminslamins:: leadingleading toto disassemblydisassembly of of nuclearnuclear
membranemembrane..
((33)) ActinActin attachmentattachment proteinsproteins:: leadingleading toto lossloss of of
attachmentattachment andand cellcell roundingrounding upup..
((44)) MicrotubulesMicrotubules andand cytoskeletoncytoskeleton proteinsproteins:: leadingleading toto
formationformation of of mitoticmitotic spindlespindle..
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DaughterDaughter cellscells shouldshould receivereceive thethe samesame
geneticgenetic informationinformation possessedpossessed byby thethe parentparentcellcell toto maintainmaintain geneticgenetic stabilitystability (( replicationreplication
mustmust bebe completecomplete andand carriedcarried outout withwith highhigh
fidelity)fidelity)..
NuclearNuclear DNADNA isis replicatedreplicated onlyonly onceonce duringduring
thethe SS phasephase ..
AA pairpair of of chromosomeschromosomes replicatesreplicates
simultaneouslysimultaneously withinwithin aa fixedfixed periodperiod of of thethe SS
phasephase..
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DNADNA integrityintegrity isis continuouslycontinuously monitoredmonitored
throughoutthroughout thethe cellcell cyclecycle inin 44 check pointscheck points . .
InIn GG11 phasephase :: Check Check DNADNA damagedamage
InIn GG22 phasephase :: Check Check DNADNA damagedamage
InIn SS phasephase :: Check Check completenesscompleteness of of replicationreplication
InIn MM phasephase :: Check Check thethe properproper chromosomalchromosomal segregationsegregation
If If thethe damagedamage couldcould bebe repairedrepaired thethe cellcell cyclecyclecontinues,continues, if if itit cannotcannot bebe repairedrepaired thethe cellcell
undergoesundergoes apoptosisapoptosis ((programmedprogrammed cellcell deathdeath))..
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ApoptosisApoptosis A
poptosisA
poptosis (dropping(dropping off)off) oror cellcell suicidesuicide isis aaprogrammedprogrammed cellcell deathdeath thatthat occursoccurs duringduring
EmbryogenesisEmbryogenesis
DevelopmentDevelopment
AdultAdult lifelife..
NecroticNecrotic cellcell deathdeath causedcaused byby cellcell injuryinjury duedue totoanoxiaanoxia oror radiationradiation..
DeathDeath receptorsreceptors onon thethe plasmaplasma membranemembrane bindbinddeathdeath signalssignals,, instructinginstructing thethe cellcell toto initiateinitiateapoptosisapoptosis..
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DeathDeath signalssignals asas tumortumor necrosisnecrosis factorfactor
(TNF)(TNF) andand FasFas--ligandligand (CD(CD 9595 L)L) bindbind thetheextracellularextracellular domaindomain of of thethe deathdeath receptorreceptor
andand thisthis allowsallows bindingbinding of of specificspecific proteinsproteins
toto thethe intracellularintracellular domaindomain andand promotespromotes aacascadecascade of of proteinprotein--proteinprotein interactionsinteractions..
ThisThis activatesactivates caspasescaspases 88 andand 99,, whichwhich thenthenactivateactivate otherother caspasescaspases..
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CaspasesCaspases areare proteasesproteases enzymes,enzymes, theythey catalyzecatalyzethethe breakdownbreakdown of of cellularcellular proteinsproteins..
TheyThey activateactivate aa specificspecific DNaseDNase calledcalled caspasecaspase--activatedactivated DNaseDNase ((CADCAD),), whichwhich hydrolyzeshydrolyzes thethe
linkerlinker DNADNA betweenbetween thethe nucleosomes,nucleosomes,
breakingbreaking thethe DNADNA intointo fragmentsfragments..
OnOn electrophoresis,electrophoresis, thesethese fragmentsfragments showshow aa
characteristiccharacteristic ladderladder appearanceappearance..
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ApoptosisApoptosis isis alsoalso causedcaused byby intracellularintracellular
stressstress..
DisruptionDisruption of of mitochondrialmitochondrial membranemembrane
leadsleads toto thethe releaserelease of of cytochromecytochrome cc,, whichwhich
alongalong withwith apoptosisapoptosis factorfactor 11 ((apaf apaf--11),),activateactivate caspasecaspase 99 andand initiatesinitiates thethe cellcell
deathdeath cascadecascade..
TheThe tumortumor suppressorsuppressor proteinprotein pp5353(unstable(unstable protein)protein) isis aa DNADNA--bindingbinding
transcriptiontranscription factorfactor becomesbecomes stabilizedstabilized byby
DNADNA damagedamage..
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MenstruationMenstruation:: EstrogensEstrogens andand progesteroneprogesterone areare thethe
mainmain stimulatorsstimulators of of endometrialendometrial growthgrowth.. WithdrawalWithdrawal
of of thesethese hormones,hormones, duedue toto atrophyatrophy of of thethe corpuscorpus
luteumluteum causescauses apoptosisapoptosis andand degenerationdegeneration of of thethe
endometriumendometrium andand precipitatesprecipitates menstruationmenstruation..
ThymusThymus glandgland atrophyatrophy:: GlucocorticoidsGlucocorticoids induceinduceapoptosisapoptosis inin thymocytesthymocytes andand causescauses atrophyatrophy of of thethe
thymusthymus glandgland inin adultadult lifelife.. ThisThis actionaction isis mediatedmediated byby
anan intracellularintracellular glucocorticoidglucocorticoid receptorreceptor..
Examples for apoptosisExamples for apoptosis
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ONCOGENESISONCOGENESIS
Definition:Definition:Conversion of aConversion of a regulated cellregulated cell into ainto a
cancerouscancerous one with uncontrolledone with uncontrolled
growth and metastasis.growth and metastasis.
Causes:Causes:
mutations or underexpression of mutations or underexpression of tumortumorsuppressor genes.suppressor genes.
mutations or overexpression of mutations or overexpression of
protooncogenesprotooncogenes..
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TUMOR SUPPR ESSOR GENESTUMOR SUPPR ESSOR GENES
Products of these genes block abnormalProducts of these genes block abnormal
growth and malignant transformation.growth and malignant transformation.
They are usually recessive; both copies of They are usually recessive; both copies of
the gene must undergo mutation to allowthe gene must undergo mutation to allow
for malignant transformation.for malignant transformation.
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1.1. The p53, p21, p16, and bax GenesThe p53, p21, p16, and bax Genes
About 50% of human cancers have a mutatedAbout 50% of human cancers have a mutated
p53 gene.p53 gene.
Cells with a mutated gene fail to undergoCells with a mutated gene fail to undergoapoptosis upon damage of DNA.apoptosis upon damage of DNA.
A mutation in the p16 gene known as multipleA mutation in the p16 gene known as multipletumor suppressor 1 (MTS 1) gene, occurs in atumor suppressor 1 (MTS 1) gene, occurs in awide variety of cancers.wide variety of cancers.
Examples of Tumor Supressor GenesExamples of Tumor Supressor Genes
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2. R etinoblastoma (R b) Gene2. R etinoblastoma (R b) Gene
TissuesTissues expressexpress R bR b genegene::
retina,retina, osteoblastsosteoblasts andand fibroblastsfibroblasts..
MutationMutation of of thethe genegene maymay bebe inheritedinherited oror acquiredacquired..
R etinoblastomaR etinoblastoma isis aa rarerare childhoodchildhood tumortumor of of thethe
retinaretina..
TheThe childchild inheritsinherits oneone mutatedmutated genegene throughthrough thethegermlinegermline andand tumortumor resultsresults fromfrom acquiredacquired
mutationmutation of of thethe remainingremaining normalnormal genegene..
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4. Genes of DNA R epair Enzymes4. Genes of DNA R epair Enzymes
Enzymes of DNA repair prevent tumorEnzymes of DNA repair prevent tumor
formation by repairing DNA.formation by repairing DNA.
Defective genes may cause tumors :Defective genes may cause tumors :
HereditaryNonpolyposis Colon Cancer (HNPCC)HereditaryNonpolyposis Colon Cancer (HNPCC)
Xeroderma PigmentosaXeroderma Pigmentosa
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ONCOGENES & PR OTOONCOGENESONCOGENES & PR OTOONCOGENES
OncogenesOncogenes
They areThey are genesgenes that causethat cause cancercancer..
Viruses causing cancer in animalsViruses causing cancer in animals
R ous sarcoma virus which causes sarcoma inR ous sarcoma virus which causes sarcoma inchickens.chickens.
It is a retrovirus with a DNA intermediate thatIt is a retrovirus with a DNA intermediate that
integrates into the host genome as a provirus.integrates into the host genome as a provirus.The viral DNA contains a gene called src (sarcomaThe viral DNA contains a gene called src (sarcoma
causing) that encodes a proteincausing) that encodes a protein--tyrosine kinasetyrosine kinase(PTK ), which phosphorylates several proteins in(PTK ), which phosphorylates several proteins intransformed cells.transformed cells.
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SomeSome virusesviruses areare oncogeniconcogenic inin humanshumans..
TheseThese includeincludeDNA DNA v
irusesv
iruses EpsteinEpstein--barrbarr virusvirus ((EBVEBV,, maymay causecause Burkitt'sBurkitt's
lymphomalymphoma andand nasopharyngealnasopharyngeal carcinoma)carcinoma)
humanhuman papillomapapilloma virusvirus ((HPVHPV,, maymay causecause cervicalcervical
carcinoma)carcinoma) hepatitishepatitis BB virusvirus ((HBV,HBV, maymay causecause HCC)HCC)
humanhuman herpesherpes virusvirus ((HHVHHV,, maymay causecause K aposiK aposi sarcoma)sarcoma)..
TheyThey alsoalso includeinclude R NA R NA virusesviruses
hepatitishepatitis CC virusvirus ((HCVHCV,, maymay causecause HCC)HCC)
humanhuman TT cellcell lymphotropiclymphotropic virusvirus ((HTLVHTLV,, maymay
causecause TT--cellcell leukemia)leukemia)..
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ProtooncogenesProtooncogenes
They areThey are normalnormal nonmalignant cells containnonmalignant cells contain
DNA DNA sequencessequences homologous to viral oncogeneshomologous to viral oncogenes..
They are active at some stage of development.They are active at some stage of development.
TheirTheir product proteinsproduct proteins are important for cellare important for cellgrowth and differentiation. They include:growth and differentiation. They include:
growth factorsgrowth factors
growth factor receptorsgrowth factor receptors signal transduction proteinssignal transduction proteins
transcription factorstranscription factors
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Causes of Conversion of aCauses of Conversion of a
protooncogene to an oncogeneprotooncogene to an oncogene
R etroviruses insert their DNA into the host genome.R etroviruses insert their DNA into the host genome.
If the viral DNA promoter or enhancer is insertedIf the viral DNA promoter or enhancer is inserted
near anear a protooncogeneprotooncogene in the host cell it becomes ain the host cell it becomes a
hyperactivehyperactive oncogeneoncogene..
An example is the insertion of a viral promoter orAn example is the insertion of a viral promoter or
enhancer near the inactiveenhancer near the inactive cc--myc genemyc gene, leading to, leading to
avian leukemiaavian leukemia..
1. Promoter or Enhancer Insertion1. Promoter or Enhancer Insertion
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2. Gene Amplification2. Gene Amplification
Increased number of copies of genes.Increased number of copies of genes.
Microscopically appear as homogeneouslyMicroscopically appear as homogeneouslystaining regionsstaining regions (HSR )(HSR ) on the chromosome oron the chromosome or
as extrachromosomal double minute (as extrachromosomal double minute (dmindmin))
chromosomes.chromosomes.
A growth factor oncogeneA growth factor oncogene ( ( hsthst ) ) is amplifiedis amplified
in some cases of breast cancer.in some cases of breast cancer.
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E rbB E rbB22 (H ER(H ER22/neu) /neu) genegene isis amplifiedamplified inin 2020--
3030%% of of humanhuman breastbreast cancercancer andand isisassociatedassociated withwith poorpoor prognosisprognosis..
NN--mycmyc isis amplifiedamplified inin neuroblastomaneuroblastoma andand isis
associatedassociated withwith poorpoor prognosisprognosis..
DihydrofolateDihydrofolate reductasereductase genegene isis amplifiedamplified inin
cancercancer patientspatients receivingreceiving methotrexatemethotrexate,, anan
inhibitorinhibitor of of thethe dihydrofolatedihydrofolate reductasereductase
enzymeenzyme..
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3. Point Mutation3. Point Mutation
R as protein (product of the ras protooncogene) isR as protein (product of the ras protooncogene) isfound in all nucleated cells.found in all nucleated cells.
It consists of theIt consists of the ss subunit of the G protein, whichsubunit of the G protein, which
has Intrinsic GTPase activity.has Intrinsic GTPase activity.
Point mutation converts this gene into ras oncogenePoint mutation converts this gene into ras oncogene
with reduced GTPase activity.with reduced GTPase activity.
The effect of growth factors acting through G proteinThe effect of growth factors acting through G protein
continues after the growth factor dissociates from thecontinues after the growth factor dissociates from the
receptor.receptor.
This mutation is observed in about 15% of cancers.This mutation is observed in about 15% of cancers.
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4. Chromosomal Translocation4. Chromosomal Translocation
R eciprocal
R eciprocal translocationtranslocation betweenbetween chromosomechromosome 99 andand
chromosomechromosome 2222 producesproduces aa fusionfusion BCR BCR --ablabl genegene thatthat encodesencodes
aa proteinprotein withwith highhigh PTK PTK activityactivity..
TheThe newnew chromosomechromosome 2222 isis knownknown asas thethe P hiladelphia P hiladelphiachromosomechromosome. .
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