Tumor Suppressor Genes - kau L3.pdfTumor Suppressor Genes • A l f A class of genes th t ll that normally suppress cell proliferation. • p53 and Rb…..ect • Mutations that inactivate

Tumor Suppressor GenesTumor Suppressor Genes

A l f th t ll • A class of genes that normally suppress cell proliferation.

• p53 and Rb…..ect

• Mutations that inactivate the tumor Mutations that inactivate the tumor suppressor gene products can release cells from growth suppression and lead to from growth suppression and lead to hyperproliferation.


•• In In 1974 1974 Knudson proposedKnudson proposedtowtow-- hits hypothesishits hypothesis

The 2 alleles on the chromosome must be inactivatedinactivated


• B th ll l f th t • Both alleles of the tumor suppressor gene must be inactivated by gene must be inactivated by

mutation for hyperproliferation to occur.


• 60% of retinoblastoma (Rb) are sporadicare sporadic

•• 4040% are familial an autosomal dominant trait% are familial an autosomal dominant trait4040% are familial, an autosomal dominant trait% are familial, an autosomal dominant trait

Th 2 ll l h 13 14 t bThe 2 alleles on chromosome 13q14 must be inactivated

Tumor Suppressor GenesTumor Suppressor Genes• Heterozygous-----one Rb gene is not

mutant

H t Rb• Homozygous------tow Rb genes are mutant =Loss of hrterozygosity of normal Rb gene


• Antigrowth signals can prevent cell proliferation by 2 mechanism:proliferation by 2 mechanism:

• 1-Cause the dividing cell go to Go.2 Th ll t t it ti diff ti t d l• 2-The cell enter post-mitotic differentiated pool & lose replicative potential

• The molecular level of antigrowth signals exertThe molecular level of antigrowth signals exert their effects on G1-S checkpoint of the cell cycle controlled by Rb genecycle, controlled by Rb gene

Normal epithelium


• Antigrowth signals can prevent cell proliferation by 2 mechanism:proliferation by 2 mechanism:

• 1-Cause the dividing cell go to Go.

2 Th ll t t it ti• 2-The cell enter post-mitotic differentiated pool & lose replicative p ppotential

TUMOR SUPPRESSOR GENES

Tumor Suppressor GenesR ti bl t GRetinoblastoma Gene

• RB gene 13q14 1st TSG discovered• Present in every somatic cell in active(hypoph.)

& inactive (hyperphosphorelated )form• Act as a brake prevent cell from moving from

G1 S • When GF stimulate cell, The cyclin D,E &CDK-

phosphorelation of RB inactivation- release th b kthe brake.

• At the same time the transcription factors E2F l d ti ti f t i tiare released- activation of transcription genes

Rb gene & cell cycleRb gene & cell cycle• Active form= break of G1-S phase

Hpophosphorylated RB geneHpophosphorylated RB gene

Inactive form= cell division G1-S phase& proliferation without additional growth p o e at o t out add t o a g o tfactor stimulation

H perphosphor lated RB geneHyperphosphorylated RB gene

Rb gene & cell cycleRb gene & cell cycle

Quiescent cells (Go& G1) contains the activecontains the active

hypophospharylated form ofhypophospharylated form of RB gene this will prevent g p

cell replication by binding & i hsequestering the

transcription factor E2Ftranscription factor E2F

Rb gene & cell cycleRb gene & cell cycleWhen quiescent cells is

i l d b hstimulated by growth factors the concentration of theconcentration of the D&E cyclins go up & result in activation of cyclincyclinD/CDK4,D/CDK6,E/CDK2 result in phosphorylation of RB result in releasesof E2F transcriptionof E2F transcription factor & transcription of several target genes


Mutations in other genes that control RBgene phosphorylation

ff fcan mimic the effect of RB lRB gene loss


Loss of normal cell cycle control i t l t li tis central to malignant

transformation & that at leasttransformation & that at least one of the four key regulators of

cell cycle is mutant in human cancercancer

CDK4, cyclin D, CDK2A, RB , y , ,

Rb gene & cell cycleRb gene & cell cycle• Mutational inactivation in tumors;

CDK2ACDK2A75% of pancreatic carcinomap40-70% of glioblastoms50% of esophageal cancer

25% of melanoma25% of melanoma20% of non small cell ca of

lung

APC GeneAPC GeneAPC ( t l i t i ) l i• APC gene (cytoplasmic protein) loss in

70-80% of colon ca, both copies must be , plost

• Inherited mutation of one allele will develop 100-1000 of adenomatous polyps in the colon by the age of 10 or 20ys. Onein the colon by the age of 10 or 20ys. One or more polyps will develop colon ca by

the age of 40 50 yrsthe age of 40-50 yrs

Tumor suppressor gene pp gAPC Gene

• APC gene (cytoplasmic protein) regulates the intracellular B catenin (which activatethe intracellular B catenin (which activate cell proliferation when WNT binds to its receptors) Anti prolifrative activityreceptors), Anti-prolifrative activity.

• In quiescent phase no WNT & B catenin is degraded by APC

• When APC is lost or mutated- B catenin• When APC is lost or mutated- B catenin is not degraded&WNT is continuously present cell proliferationpresent cell proliferation

APC Gene• APC gene loss lead to tumor development,

both copies must be lost.both copies must be lost.• Seen in70-80% of sporadic colon ca

APC ma be normal b t B catenin m tated• APC may be normal but B catenin mutated• Inherited mutation of one allele will

develop 100-1000 of adenomatous polyps in the colon by the age of 10 or 20ys. One or more polyps will develop colon ca by the age of 40ys (Familial Polyposis coli)

• APC mutation lead to adenoma and more mutation are needed for ca to develop

P53P53

TP53TP53• Main functions;• Main functions;

Antiproliferative effectpRegulate apoptosis

Trigger of TP53 pathway is:anoxiaanoxia

inappropriate oncogene expressioninappropriate oncogene expression MYC

damage of DNA

TP53TP53• NormalTP53 in non stressed cell is

short 20 min. due to association to MDM2 protein that regulate its g

destruction.• Unshackled from MDM2, TP53 becomeUnshackled from MDM2, TP53 become

activated as a transcriptional factor• Dozens of genes whose transcription is• Dozens of genes whose transcription is

triggered by TP53 that is grouped in 2 categoriescategories

-cause cell cycle arrest-cause appoptosis

TP53TP53• If DNA repair is successful,TP53 up

regulates transcription of MDM2 which g pdown regulates P53 reliving cell cycle blockblock

• DNA repair is not completely understood one DNA damage sensorunderstood one DNA damage sensor is ATM protein

TP53TP53• TP53 sense DNA damage & assist in

the repair of DNA by causing G-1the repair of DNA by causing G 1arrest & inducing DNA repair gene

• Cells cannot repair DNA will undergoesCells cannot repair DNA will undergoes apoptosis

Documents

Tumor Suppressor Genes - kau L3.pdfTumor Suppressor Genes • A l f A class of genes th t ll that normally suppress cell proliferation. • p53 and Rb…..ect • Mutations that inactivate