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BY DR.B.NANDITHA

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Proto-oncogenes

Tumorsuppressorgenes

Cellcycleregulators

DNA repairgenes

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Genesthat promoteautonomouscellgrowth

incancercells.

TheirnormalcellularcounterpartsarecalledPROTO ONCOGENES. Theyare physiologicalregulatorsofcell proliferationanddifferentiation.

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Mutantallelesofproto-oncogenesDominant

Tumorsuppressorgenesrecessiveoncogenes.

Haplo-insufficiency (fewtumorsuppressor

genes)

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Threelettercode

Generallyrepresentsthecancerinwhichthey

werefirstidentified. Ex: RAS RAtSarcomas

MYC avianMYelocytomatosis.

Prefix:

c- cellu

lar,v- viral,

others

(n-

myc:

neuroblastoma)

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Thefirstoncogenewasdiscoveredin 1970 andwastermedsrc (asinsarcoma). Srcwasinfactfirstdiscoveredasanoncogeneinachickenretrovirus. Experiments performedby

DrSteve martinoftheUniversityofCalifornia, BerkeleydemonstratedthattheSRCwasindeedtheoncogeneofthevirus.

In 1976 Drs. J.Michael Bishop andHaroldE. Varmus oftheUniversityofCalifornia,San Francisco demonstratedthat

oncogenesweredefective proto-oncogenes,foundin manyorganismsincludinghumans. Forthisdiscovery Bishop andVarmuswereawardedtheNobelPrize in 1989.

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Abilityto promotecellgrowthintheabsenceofnormal mitogenicsignals.

Their productsarecalledONCOPROTEINS. Theyaredevoidofregulatoryelements. Theirproductionisconstitutive.

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Growth factor binds

checkpointcheckpoint

(cyclinD/CDK4)

(cyclinE/CDK2)

Cyclin A/CDK2)

Cyclin B/CDK1)

Quiescent cell-G0

committed cell

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Growth factor binds

checkpointcheckpoint

(cyclinD/CDK4)

(cyclinE/CDK2)

Cyclin A/CDK2)

Cyclin B/CDK1) P53P53

P27

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Growthfactorbindstoreceptor Transientactivationofreceptor S

ignaltransduction Activationofnuclearregulatoryfactors Cellcycle Celldivision

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(RTK)

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Growthfactors

Growthfactorreceptor

Signaltransducers Nuclearregulatory proteins

Cellcycleregulators

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GROWTH FACTORS:PDGF : SIS (astrocytoma,osteosarcoma)FGF : HST 1, INT 2 (stomach,bladder,breast,melanoma)

TGF : TGF (astrocytoma,hepatocellular)

HGF : HGF (thyroid)

GROWTH FACTOR RECEPTORS:EGFR :ERB-B1 (sqcellcalung,gliomas), ERB-B2(breast,ovarian)

Neurotrophicfactor R: RET (MEN 2, medullarycathyroid)PDGF R : PDGF-R (gliomas)

Stem cellfactor R : KIT (GI stromaltumors)

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SIGNAL TRANSDUCTION PROTEINS:GTPbinding : K-RAS, H-RAS, N-RAS (colon,lung,pancreas)Nonrecepor Tyrosinekinase:ABL (CML, ALL)

NUCLEAR REGULATORY PROTEINS:Transcriptionalactivators :C-MYC, N-MYC, L-MYC

(burkitts,neuroblastoma,smallcelllung)

CELL CYCLE REGULATORSCyclins : CYCLIN-D ,CYCLIN-E (lymphomas,breast,oesophagus)

Cyclindependantkinase:CDK-4

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AGENTS CAUSING ACTIVATION

Viruses,radiation

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Point mutation

Amplification

Overexpression Translocation

Viruses

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RET :Multipleendocrineneoplasia II

K-RAS:Colon,lung,pancreatic

H-RAS: Bladder,kidney N-RAS:Melanomas,hemat malignancies

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N-MYC: Neuroblastoma,smallcellca Lung L-MYC:smallcellca

Erb-b2 :breast,ovarian

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ERB-B1 (EGFR):Squamouscellcalung,gliomas SIS (PDGF):Astrocytoma

TG

F :

Astrocytoma HST 1 (FGF):stomachca CyclinE: Breastca

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ABL :Chronic myeloidleukemia

C-myc: Burkittslymphoma

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Oncogeneinsertionv-sis:Simiansarcomavirus.oncoprotein

resemblingb-PDGF.

Insertionofpromoter/enhancerInt-2: mouse mammarytumor

virus.enhances productionofFGF.

EBV-burkittslymphoma, HPV-cervix

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Proteinsthatapplybreakstocell proliferationare productsoftumor suppressor genes.

Both genes need to be inactivated fortumorigenesis. KNUDSONS 2 HIT THEORYOne genetic change inherited from affected

parent, other is acquired.

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TGFTGF--b receptorb receptor Growth inhibitionGrowth inhibition coloncolon

NFNF--11 Inhibits rasInhibits ras Neurofibromatosis1,neNeurofibromatosis1,neuroblastomas,sarcomauroblastomas,sarcoma

APCAPC Inhibits signalInhibits signaltransductiontransduction FAP,stomach,pancFAP,stomach,pancreasreas

PTENPTEN Inhibits signalInhibits signaltransductiontransduction

Endometrial,prostaEndometrial,prostatete

RB (RB (Chromosome 13)Chromosome 13)Cell cycle regulatorCell cycle regulator Retinoblastoma,osteosRetinoblastoma,osteos

arcomaarcoma

PP--5353 (17)(17) Apoptosis in responseApoptosis in responseto DNA damageto DNA damage

Most cancers,LiMost cancers,Lifraumeni syndromefraumeni syndrome

WTWT--11 ( 11 )( 11 ) Nuclear transcriptionNuclear transcription Wilms tumorWilms tumor

BRCABRCA--1,21,2 (17,13)(17,13) DNA repairDNA repair Breast, ovaryBreast, ovary

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P 53 gets activated

P 21-(CDK inhibitor)G1 arrest

GADD45: DNA repair BAX: apoptosis

If repair fails

(SENSED- ATM)

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Principle usedin RT:radiationinduced DNAdamage-p53 mediatedapoptosis.

Tumorswith mutated p-53a

re LESSSENSITIVEto chemo and radiotherapy.(lung,colorectal)

Tumorswithintact p 53 are more sensitive to chemo

and radiotherapy.(testicular tumors, childhoodALL)

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Selfsufficiencyingrowthsignals Insensitivitytoanti-growthsignals: (p53,

TGF-b,RTK,ras,RB, APC, myc) Resistancetoapoptosis:(bcl2,PTEN ,caspases) Inductionandsustaining

angiogenesis:(VEGF,PDGF,FGF..) Tissueinvasionand

metastasis:(integrins,cadherins,MMPs) Limitlessreplicative potential:(p53,RB,telomerase)

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