Tumor supressor genes
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Tumor suppressor genes normally inhibit cell growth but can be inactivated through mutations, leading to cancer. The retinoblastoma (RB) gene was the first tumor suppressor gene discovered. According to Knudson's two-hit hypothesis, both copies of the RB gene must be inactivated for retinoblastoma to develop, either through two spontaneous mutations or one inherited mutation plus another acquired mutation. The RB protein regulates the cell cycle by binding to the E2F transcription factor and preventing cell cycle progression. RB can be inactivated through mutations in the gene, overexpression of cyclin-dependent kinases, or viral oncoproteins like HPV E7 binding RB instead of E2F. Cancers associated with
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Tumor supressor genes
- 1. TUMOR SUPRESSOR GENES Insensitivity to Growth Inhibition
- 2. Learning outcomes • Tumor suppression genes- general aspects • Retinoblastoma gene • Knudson’s two Hit Hypothesis • Role of RB in regulation of cell cycle • Mechanism of inactivation of RB • Tumors associated with RB gene mutations
- 3. Tumor suppressor genes(TSG) •Tumor suppressor proteins( products of TSG) •Regulate cell growth by applying brakes to cell proliferation ( Growth Inhibition) •Failure of growth inhibition is seen in carcinogenesis •Loss of function of these genes is a key event in carcinogenesis
- 4. Gene Location Assoc. Human tumors 1. RB Nucleus(13q14) Retinoblastoma Osteosarcoma 2. TP53 Nucleus(17p13) Ca lung,colon. head, neck & breast 3. APC Cytosol Ca colon 4. Others -WT1&2 -NF1&2 -BRCA1&2 Nucleus Plasma membrane Nucleus Wilm’s tumor Neurofibromatosis 1 & 2 Ca breast, ovary
- 5. Loss of Heterozygosity Both Normal alleles of Tumor Suppressor gene(TSG) One normal allele(active) another abnormal allele(inactive) of TSG Both abnormal alleles ( inactive ) of TSG heterozygous Loss of heterozygosity Normal Function of Tumor Suppressor Gene ( TSG) Normal Function of Tumor Suppressor Gene ( TSG) Loss of Function of Tumor Suppressor Gene ( TSG) TUMOR Deletion Mutation
- 6. Retinoblastoma Gene ( RB Gene) • First discovered Tumor suppressor gene • Chromosome 13q14 • Retinoblastoma: is a childhood tumor with inactivation of this gene.
- 7. Knudson’s two-hit hypothesis • Two mutations ( hits) involving both the alleles of TSG ( here RB gene) is a basic requisite for the development of tumor • Retinoblastoma can occur as hereditary or sporadic form • Explanation for the same is given by Knudson’s two-hit hypothesis
- 8. Hereditary Retinoblastoma Sporadic Retinoblastoma 1st Hit Inherited Mutation 2nd Hit Acquired Mutation 1st Hit Acquired Mutation 2nd Hit Acquired Mutation Knudson’s two-hit hypothesis
- 9. RB Gene • RB protein- product of RB gene • Key role in regulation of the cell cycle • “Governor” of the cell cycle
- 10. M S G1G2 Gap 1 Gap 2 Cells crossing this will have to complete mitosis RB acts here !
- 11. E2F Transcriptional Activation G1 – S phase
- 14. Histone Methyl Transferase Histone Deacetylase Chromatin Remodeling factors Transcription No Progression to S phase Hypophosphorylated RB
- 15. E2F Hyperphosphorylated RB Cyclin D- CDK4 Cyclin D- CDK 6 Cyclin E-CDK2
- 16. Transcriptional Activation G1 – S phase E2F
- 19. So, How does RB gets inactivated ? Or How does the Antiproliferative activity of RB is nullified? 1. Germline & somatic Loss of function Mutations of RB Gene 2. Gene Amplifications of CDK 4 and Cyclin D genes
- 20. 3. Functional inactivation of RB • HPV 16 HPV E7 protein ( Viral Oncoprotein) Binds to same RB pocket that sequesters E2F Functional inactivation of RB Release of E2F Multiplication of cells Cervical Carcinoma
- 21. Tumors associated with RB Gene mutations 1. Retinoblastoma 2. Osteosarcoma 3. Glioblastomas 4. Small cell carcinomas of lung 5. Breast cancers & 6. Bladder cancers
- 22. Summary • Tumor suppression genes • Retinoblastoma gene • Knudson’s two Hit Hypothesis • Role of RB in regulation of cell cycle • Mechanism of inactivation of RB • Tumors associated with RB gene mutations