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What are tumor suppressor genes?Repression of genes that are essential for the continuing of thecell cycle.Coupling the cell cycle to DNA damage. As long as there isdamaged DNA in the cell, it should not divide.If the damage cannot be repaired, the cell shouldinitiate apoptosis (programmed cell death)Some proteins involved in cell adhesion prevent tumor cells fromdispersing, block loss of contact inhibition, and inhibit metastasis.These proteins are known as metastasis suppressors
Categories of tumor suppressor genes Caretaker genes:Maintain the integrity of the genome by repairing DNA damage Gatekeeper genes:Inhibit the proliferation or promote the death of cells withdamaged DNA
Tumor suppressor genes: functional categories and tumorassociationCategory Gene Function Tumor susceptibilityif germ linemutationCommentsGatekeepersp53 TranscriptionfactorLi-FraumenisyndromeAlso mutated in 50%of human cancersRb1 TranscriptionalregulatorFamilialretinoblastomaOften mutated inother cancersAPC Regulates β-catenin functionFamilialadenomatuspolyposisOften mutated insporadic colorectalcancersCaretakersBRCA1DNA repair Breast and ovariancancerRarely mutated insporadic breastcancersBRCA2DNA repair Breastcancer(female andmale)
Retinoblastoma(Rb) gene First phenotypic cancer suppressor gene to be discovered Responsible for retinoblastoma, a malignant tumor of retina, a rarechildhood tumor 60% are sporadic, remaining ones are familial
Two-hit hypothesis To account for the sporadic and familial occurrence ofretinoblastoma, Knudson, in 1971– Two mutations(hits) are required with Rb gene ,located 13q14, for the development of retinoblastoma– In familial cases, children inherit a defective copy ofRb gene, the other copy is normal. Retinoblastomadevelops when the normal copy undergo somaticmutationRecessive disorder, Transmitted as dominant trait– In sporadic cases, both normal Rb alleles are lost bysomatic mutation in one of the retinoblasts.
The “two-hit" origin of retinoblastoma
p53 Gene Situated at the short arm of the chromosome 17 Mutated in most of the cancer cases Normal functions p53 It can activate DNA repair proteins when DNA has sustaineddamage. It can arrest growth by holding the cell cycle at the G1/S regulationpoint on DNA damage recognition (if it holds the cell here for longenough, the DNA repair proteins will have time to fix the damage andthe cell will be allowed to continue the cell cycle). It can initiate apoptosis, the programmed cell death, if DNA damageproves to be irreparable.
p53 Gene P53 level raise in cells with sustained cell damage, untilthe damage is repaired or cell undergoes apoptosis Prevents propagation of possibly mutated cells Called “the guardian of the genome”
p53 Gene P53 can lost its function by:Non-sense mutation or mis-sense mutationComplex of normal p53 and mutant p53 inactivating thefunction of normal alleleBinding of normal p53 to viral oncoproteins
Role of p53 in cells with damaged DNA
Li-Fraumeni syndrome Refers to the inherited predisposition to develop cancers in many organsowing to germ line mutations of p53 Affected individuals Carry germ line mutation in one p53 allele, buttumors display mutation at both alleles Another example of two-hit hypothesis
Other tumor suppressor genes
APC Gene Implicated in familial adenomatous polyposis coli and mostsporadic colorectal cancers APC binds to and inhibits the function of β-catenin β-catenin activates certain transcription factors that activatesseveral genes including myc and cyclin D Mutant APC is unable bind β-catenin to down regulate its activity
WT-1 gene Is deleted in hereditary Wilms tumor(WT) It codes for a DNA-binding protein that represses transcription ofPDGF,IGF-I and abl2, which promotes growth Loss of WT-1 gene expression also occur in many breast cancers
NF-1 gene Germ line mutation in type 1 neurofibromatosis(NF) Encode neurofibromin, a negative regulator of ras Inactivation of NF-1 permits unopposed ras, thereby promotes cellgrowth
von Hippel-Lindau (VHL) gene Inactivation results in VHL syndrome, which is associated withrenal cell carcinoma, hemangioblastoma of the brain,pheochromocytoma Normal VHL protein complexes with and inhibit elongin,a moleculethat promotes transcriptional elongation of growth promotinggenes
P15 and p16 genes Inactivation identified primarily in breast, pancreas and prostatetumors. The gene products are cdk inhibitors and serve as the negativeregulators of the cell cycle
BRCA1 and BRCA2 genes Brest(BR) cancer(CA) susceptibility genes, also incriminated insome ovarian cancers Involved in G1 check point Block entry of cell into S phase, particularly by inducing CDKinhibitor p21 Promote DNA repair by binding to RAD51
PTEN geneTermed phosphatase and tensin homologueMutated in most prostate cancers and manyglioma and thyroid cancersThe gene product suppresses tumor growth byantagonising tyrosine kinasesRegulates invasion and metastasisGerm line mutation responsible for Cowdensyndrome Multiple hamartoma Increased risk of cancers of the breast, thyroid and endometrium