cell cycle,apoptosis,oncogenesis

8/6/2019 cell cycle,apoptosis,oncogenesis

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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)..



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.



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 . .





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.



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



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.



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





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



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..





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..



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))..





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..



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..





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..



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..







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



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..



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.



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



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..





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



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.



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)..



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



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





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.



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..





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.



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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cell cycle,apoptosis,oncogenesis