Tumor Suppressor Genes

Tumor Suppressor Genes : 

Tumor Suppressor Genes

What are tumor suppressor genes? : 

What are tumor suppressor genes? Responsible for the inhibitory control of cellular replication Clue to the existence: Transformed cells fused with untransformed cells Resulting hybrid cells behaved like untransformed cells until the inhibitory genes were lost Mutation in inhibitory genes revert the untransformed hybrid cells back to the transformed stage

Categories of tumor suppressor genes : 

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 with damaged DNA

Retinoblastoma(Rb) gene : 

Retinoblastoma(Rb) gene First phenotypic cancer suppressor gene to be discovered Responsible for retinoblastoma, a malignant tumor of retina, a rare childhood tumor 60% are sporadic, remaining ones are familial

Two-hit hypothesis : 

Two-hit hypothesis To account for the sporadic and familial occurrence of retinoblastoma, Knudson, in 1974 Two mutations(hits) are required with Rb gene , located 13q14, for the development of retinoblastoma In familial cases, children inherit a defective copy of Rb gene, the other copy is normal. Retinoblastoma develops when the normal copy undergo somatic mutation Recessive disorder, Transmitted as dominant trait In sporadic cases, both normal Rb alleles are lost by somatic mutation in one of the retinoblasts.

The “two-hit" origin of retinoblastoma : 

The “two-hit" origin of retinoblastoma

p53 Gene : 

p53 Gene Situated at the short arm of the chromosome 17 Mutated in most of the cancer cases Normal functions p53 Repair of damaged DNA before S-phase in the cycle by arresting the cell cycle in G1 until the damage is repaired Apoptotic cell death if there is extensive DNA damage

p53 Gene : 

p53 Gene P53 level raise in cells with sustained cell damage, until the damage is repaired or cell undergoes apoptosis Prevents propagation of possibly mutated cells Called “the guardian of the genome”

p53 Gene : 

p53 Gene P53 can lost its function by: Non-sense mutation or mis-sense mutation Complex of normal p53 and mutant p53 inactivating the function of normal allele Binding of normal p53 to viral oncoproteins

Role of p53 in cells with damaged DNA : 

Role of p53 in cells with damaged DNA

Li-Fraumeni syndrome : 

Li-Fraumeni syndrome Refers to the inherited predisposition to develop cancers in many organs owing to germ line mutations of p53 Affected individuals Carry germ line mutation in one p53 allele, but tumors display mutation at both alleles Another example of two-hit hypothesis

Other tumor suppressor genes : 

Other tumor suppressor genes

APC Gene : 

APC Gene Implicated in familial adenomatous polyposis coli and most sporadic colorectal cancers APC binds to and inhibits the function of β-catenin β-catenin activates certain transcription factors that activates several genes including myc and cyclin D Mutant APC is unable bind β-catenin to down regulate its activity

WT-1 gene : 

WT-1 gene Is deleted in hereditary Wilms tumor(WT) It codes for a DNA-binding protein that represses transcription of PDGF,IGF-I and abl2, which promotes growth Loss of WT-1 gene expression also occur in many breast cancers

NF-1 gene : 

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 cell growth

von Hippel-Lindau (VHL) gene : 

von Hippel-Lindau (VHL) gene Inactivation results in VHL syndrome, which is associated with renal cell carcinoma, hemangioblastoma of the brain, pheochromocytoma Normal VHL protein complexes with and inhibit elongin,a molecule that promotes transcriptional elongation of growth promoting genes

P15 and p16 genes : 

P15 and p16 genes Inactivation identified primarily in breast, pancreas and prostate tumors. The gene products are cdk inhibitors and serve as the negative regulators of the cell cycle

BRCA1 and BRCA2 genes : 

BRCA1 and BRCA2 genes Brest(BR) cancer(CA) susceptibility genes, also incriminated in some ovarian cancers Involved in G1 check point Block entry of cell into S phase, particularly by inducing CDK inhibitor p21 Promote DNA repair by binding to RAD51

PTEN gene : 

PTEN gene Termed phosphatase and tensin homologue Mutated in most prostate cancers and many glioma and thyroid cancers The gene product suppresses tumor growth by antagonising tyrosine kinases Regulates invasion and metastasis Germ line mutation responsible for Cowden syndrome Multiple hamartoma Increased risk of cancers of the breast, thyroid and endometrium

Thank you : 

Thank you