Tumor Suppressor Genes A class of genes that normally suppress cell proliferation. p53 and Rb..ect Mutations that inactivate the tumor suppressor gene products can release cells from growth suppression and lead to hyperproliferation.
Tumor Suppressor Genes In 1974 Knudson proposed tow- hits hypothesis The 2 alleles on the chromosome must be inactivated
Tumor Suppressor Genes Both alleles l of the tumor suppressor gene must be inactivated by mutation for hyperproliferation to occur.
Tumor Suppressor Genes 60% of retinoblastoma (Rb) are sporadic 40% are familial, an autosomal dominant trait Th 2 ll l h 13 14 tb The 2 alleles on chromosome 13q14 must be inactivated
Tumor 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
Tumor Suppressor Genes Antigrowth signals can prevent cell proliferation by 2 mechanism: 1-Cause the dividing cell go to Go. 2-The cell enter post-mitotic ti differentiated t d pool & lose replicative potential The molecular level of antigrowth signals exert their effects on G1-S checkpoint of the cell cycle, controlled by Rb gene
Normal epithelium
Tumor Suppressor Genes Antigrowth signals can prevent cell proliferation by 2 mechanism: 1-Cause the dividing cell go to Go. 2-The cell enter post-mitotic ti differentiated pool & lose replicative potential
TUMOR SUPPRESSOR GENES
Tumor Suppressor Genes Retinoblastoma t Gene RB gene 13q14 1 st 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 the brake. At the same time the transcription factors E2F are released- activation of transcription ti genes
Rb gene & cell cycle Active form= break of G1-S phase Hpophosphorylated RB gene Inactive form= cell division G1-S phase& proliferation o without additional a growth factor stimulation Hyperphosphorylated RB gene
Rb gene & cell cycle Quiescent cells (Go& G1) contains the active hypophospharylated form of RB gene this will prevent cell replication by binding & sequestering the transcription factor E2F
Rb gene & cell cycle When quiescent cells is stimulated by growth factors the concentration of the D&E cyclins go up & result in activation of cyclin D/CDK4,D/CDK6,E/C DK2 result in phosphorylation of RB result in releases of E2F transcription factor & transcription of several target genes
Rb gene & cell cycle Mutations in other genes that control RB gene phosphorylation can mimic the effect of RB gene loss
Rb gene & cell cycle Loss of normal cell cycle control is central to malignant transformation & that at least one of the four key regulators of cell cycle is mutant in human cancer CDK4, cyclin D, CDK2A, RB
Rb gene & cell cycle Mutational inactivation in tumors; CDK2A 75% of pancreatic carcinoma 40-70% of glioblastoms 50% of esophageal cancer 25% of melanoma 20% of non small cell ca of lung
APC Gene APC gene (cytoplasmic protein) loss in 70-80% of colon ca, both copies must be lost 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 40-50 yrs
Tumor suppressor gene APC Gene APC gene (cytoplasmic protein) regulates the intracellular B catenin (which activate cell proliferation when WNT binds to its receptors), Anti-prolifrative activity. In quiescent phase no WNT & B catenin is degraded by APC When APC is lost or mutated- B catenin is not degraded&wnt is continuously present cell proliferation
APC Gene APC gene loss lead to tumor development, both copies must be lost. Seen in70-80% of sporadic colon ca 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
P53
Main functions; TP53 Antiproliferative effect Regulate apoptosis Trigger of TP53 pathway is: anoxia inappropriate oncogene expression MYC damage of DNA
TP53 NormalTP53 in non stressed cell is short 20 min. due to association to MDM2 protein that regulate its destruction. Unshackled from MDM2, TP53 become activated as a transcriptional factor Dozens of genes whose transcription is triggered by TP53 that is grouped in 2 categories -cause cell cycle arrest -cause appoptosis
TP53 If DNA repair is successful,tp53 up regulates transcription of MDM2 which down regulates P53 reliving cell cycle block DNA repair is not completely understood one DNA damage sensor is ATM protein
TP53 TP53 sense DNA damage & assist in the repair of DNA by causing G-1 arrest & inducing DNA repair gene Cells cannot repair DNA will undergoes Cells cannot repair DNA will undergoes apoptosis