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8/3/2019 Oncogenes 2
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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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