Tumour suppressor genes

Tumour suppressor genes

1. Dr.DhanyaKC
Assistant Professor
Department of Microbiology
St. Mary’s College,
Thrissur-680020
Kerala

2. •Cancerisageneticdiseaseandismostlycausedbysomatic
mutations.
•Thecharacteristicpropertiesofcancercells-consequencesof
geneticchangesinthetumorcells-Genomicinstability
•Self-sufficientproliferationofgrowth
•Refractorytoinhibitorysignals
•Survivalwithoutsurvivalsignals
•Unlimitedreplicativepotential
•Recruitmentofbloodsupply
•Invasionandmetastasis
•Cancercellscontainmultiplealterationsinthenumberandstructure
ofgenesandchromosomes,mainlyacquiredbymutationsinsomatic
cells.
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

3. Individualgenesdisplaypointmutationssuchasbasechanges,
insertionsanddeletions,orcanbeaffectedbychromosomal
translocationsorinversions.
Thesechangesleadtothe
expressionofalteredgeneproducts,
decreasedorincreasedgeneexpression
novelgeneproductslikefusionproteins.
Twoclassesofgenesaffectedbygeneticandepigeneticalterationsin
cancercellsareoncogenesandtumorsuppressorgenes.
Oncogenescontributetotumordevelopmentbyincreasedor
misdirectedactivity.
Tumorsuppressors-insufficientorlostfunctionsupportstumor
development.
Typically,inhumancancersactivationofoncogenesandinactivation
oftumorsuppressorgenes-bothareobserved.
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

4. Oncogenes
Stimulate Proliferation
Inhibit Differentiation
Inhibit Apoptosis
Tumor Suppressor Genes
Inhibit Proliferation
Promote Differentiation
Stimulate Apoptosis
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

5. Oncogenesarecellularorviral(i.e.,insertedintothecellbyavirus)
genes;theirexpressioncancausethedevelopmentofcancer.
Proto-oncogenesarenormalcellulargenes-conversiontooncogenes
occurviaseveralmechanisms.Gain-of-functionmutationsofproto-
oncogenesstimulatecellstomultiply.
Tumorsuppressors(anti-oncogenes)arecellulargenes;their
inactivationincreasestheprobabilityoftumorformation.Loss-of-
functionmutations-relievecellsofcontrolinreplication.
Aboutonehundredpotentialoncogenes(cellularandviral)andthirty
tumorsuppressorshavebeenrecognized.
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

6. TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

7. Tumor Suppressor Genes
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

8. TumorsuppressorsareguardiansagainstDNAdamage.
•Slowsorinhibitscellproliferationandpreventsdamagedor
abnormalcellsfrombecomingmalignant.
•MonitorDNAdamageandhelprepairthedamagebeforecells
divide.
•InducegrowtharrestattwoDNAdamagecheckpoints:thefirstgap
phase(G1)andthesecondgapphase(G2)ofthecellcycle.This
enablescellstochecktheintegrityofthechromosomesbefore
proceedingintoDNAreplication(Sphase)ordivision(Mphase).
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

9. Functions of tumor-suppressor proteins
Repressionofgenesthatareessentialforthecontinuingofthecellcycle,
effectivelyinhibitingcelldivision.
CouplingthecellcycletoDNAdamage.Cellshouldnotdividewith
damagedDNA-thecellcyclecontinueonceitisrepaired.
Ifthedamagecannotberepaired,thecellshould
initiateapoptosis(programmedcelldeath)toremovethethreatitposesfor
thegreatergoodoftheorganism.
Metastasissuppressorspreventtumorcellsfromdispersing,blockloss
ofcontactinhibition,andinhibitmetastasis.
DNArepairproteinsareusuallyclassifiedastumorsuppressors.
HNPCC,MEN1andBRCA.
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

10. ThefunctionalinactivationoftumorsuppressorsbyGenetic(gene
mutationordeletion,mutationsinthepromoterofgenes)orepigenetic
alterations(promotermethylation,mutationsinthepromoterofgenes)–
createsimbalancebetweenproliferation,celldeath,and
differentiationprogramsthatfacilitatestumorigenesis.
Individualsbornwithmutationsintumor-suppressorgenesare
predisposedtocancer.
Tumorsuppressorsrepresentabout0.001%ofthetotalnumberof
genes(around30,000)thatmakeuptheentiremammaliangenome.
About30tumorsuppressorsareknown.
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

11. THE “TWO HIT” HYPOTHESIS: LOSS OF HETEROZYGOSITY
TheKnudsonhypothesis-canceristheresultofaccumulatedmutationsto
acell'sDNA.
Twomutationsarerequiredforthedevelopmentofretinoblastoma
Familialretinoblastoma
Mutatedallelefromoneparent(thefirsthit)inretinoblastoma(RB)gene-
Heterozygosity-notsufficienttocausetumor-childisinitially
asymptomatic.
AsecondmutationordeletionontheotherRBallele(secondhit)-lossof
functionofbothalleles–lossofheterozygosity(LOH)–developmentof
tumor.
Nonfamilialor“sporadic”retinoblastoma
Somaticmutationsonbothalleles(twohits)inretinalcells-diseaseisnot
transmittedtothenextgeneration.
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

12. TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

13. HAPLOINSUFFICIENCY IN CANCER
Appearanceofaphenotypeincellsoranorganismwhenonlyoneof
thetwogenecopies(alleles)isinactivated.
Forsometumorsuppressorgenes,thelossofasinglealleleis
sufficienttoinducesusceptibilitytotumorformation-theseare
haploinsufficienttumor-suppressorgenes.
Inactivationofoneallelecanbeachievedbygenetic(i.e.mutationor
deletion)orepigenetic(transcriptionalsilencingbymethylation,repressor
complexes,ormutationsinthepromoterregion)events.
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

14. EPIGENETIC EVENTS
Epigeneticregulationofgenes-methylation,repressorcomplexes,or
mutationsofthepromoterregions–reducemessengerRNA
transcription-reductionorlossofproteinexpression.
MethylationoccursonthecytosinenucleotideofCpGpairsusually
locatedinpromoterregions,resultingintranscriptionalsilencing.
Mutationsinthepromoterregioncanaffectbindingoftranscription
factorstospecificDNAbindingdomains.
Repressorproteincomplexesbindtothepromoterregionsof
affectedgenes-Transcriptionalrepression.
Epigeneticeventsarelinkedtocancerdevelopmentandareequally
importantintheprocessofcarcinogenesis.
Eg.tumorsuppressorp16INK4Aorp14ARF-silencedbymethylation
oftheirpromotersorbyactivetranscriptionalrepressionbyrepressor
proteincomplexes.
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

15. RETINOBLASTOMAPROTEINisimportantinthecontrolofproliferationand
developmentofnotonlyretinalcells,butalsoothertissues.
Retinoblastoma-largedeletionsofcodingexonsorpointmutations-loss
ofthemessengerRNAortheexpressionofanonfunctionalpRbprotein.
Childrenwithgerm-lineRBmutationsareathigherriskofdeveloping
osteosarcomaslaterinadolescence.
CertainsporadichumantumorswithRBmutations-carcinomasofthe
bladder,breast,andinparticularsmall-celllungcarcinomas.
Theretinoblastomaproteinplaysacriticalroleinthecontrolofneoplasiain
avarietyoftissues.
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

16. TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

17. p53/TP53“The guardian of the genome” -a transcription factor –
its loss leads to genomic instability and increased mutagenesis.
Restrainsuncontrolledcellgrowth–blockcellcycleandinduce
apoptosis.
Sensemultiplecellularstresses(genotoxicstresse.g.,UV,X-ray,carcinogens,
andcytotoxicdrugs)oroncogenicstresses(hyperproliferativesignalsfrom
oncogenes).
Inresponsetostress,thep53proteinisstabilizedandactivated-
induceasetofgenesinvolvedincellcyclearrest,DNArepair,or
apoptosis.
p53isinactivatedinmosthumancancers(50%oftumors)asaresultofmutations
intheTP53gene,orthroughbindingtoviralproteins.
Tumorsuppressoractivityofp53isduetoitsabilitytoinduceapoptosis
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

18. TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

19. TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

20. ThephosphatasePTEN(phosphataseandtensinhomolog)negatively
regulatescellproliferation.
LossofPTENfunctioniscommoninseveralcancertypes.
SomaticinactivatingmutationsinPTENarefrequentlyfoundin
glioblastoma,endometrialcarcinoma,andprostateadenocarcinoma,
insporadiccancersofthebreast,thyroid,lung,stomach,andblood.
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

21. TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

22. TheGTPaseNF-1
NF-1isaGTPase-negativelyregulatesRassignaling.
Ras-mediatorofproliferativesignalsinresponsetoreceptor
activation-itsunrestrictedactioninduceshyperproliferativesignals.
ActivatedRas-GTPisinactivatedtoRas-GDPbyNF-1
Mutatedinneurofibromatosisandgliomas.
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

23. TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

24. BRCA1andBRCA2aretumorsuppressorgenesandareinvolved
inDNArepairofdouble-strandbreaks.
MutationsinBRCA1(chromosome17)and/orBRCA2(chromosome
13)causedecreasedstabilityofthehumangenomeandresultin
dangerousgenerearrangementsthatcanleadtohematologic
cancers.
ABRCAmutationisamutationineitherofthe
genes,BRCA1andBRCA2.
HeterozygousgermlinemutationsineithertheBRCA1orBRCA2
genes-highriskforbreastandovariancancerphenotypes-
exhibitlossofheterozygosity(LOH).
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

25. TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

26. TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

27. REGRESSING TUMORS BY ACTIVATING TUMOR SUPPRESSOR GENES
–A THERAPEUTIC TARGET
Preclinical studies both in vitro and in vivo have shown that restoring
p53 function can induce apoptosis in cancer cells.
P53 gene therapy for lung cancer, hepatocellular carcinoma using
viral delivery system.
However, resistance develops in many patients, suggesting that
combination of such gene-targeted therapies may be required.
TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur

28. TumorSuppressor genes, Dr.DhanyaKC, St.Mary'sCollege, Thrissur