Tumour supressor gene


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This ppt.. helps to study how the tumour suppressor gene helps to control the tumour growth.

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Tumour supressor gene

  2. 2. Tumor Suppressor Genes Guided by Dr.DE.Salamun
  3. 3. TUMOR  A tumor, also known as a neoplasm, is an abnormal mass of tissue which may be solid or fluid-filled.  A tumor does not mean cancer - tumors can be benign (not cancerous), pre-malignant (pre-cancerous), or malignant (cancerous).
  4. 4. CANCER  The name for diseases in which the body's cells become abnormal and divide without control.  They may spread through the bloodstream and lymphatic system to other parts of the body.
  5. 5. WHAT IS TUMOR SUPPRESSOR GENE ?  Tumor suppressor genes are genes that regulate the growth of cells. When these genes are functioning properly, they can prevent and inhibit the growth of tumors.  When tumor suppressor genes are altered or inactivated (due to a mutation), they lose the ability to make a protein that controls cell growth.
  6. 6. 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
  7. 7. Tumor suppressor genes: functional categories and tumor association Category Gene Function Tumor susceptibility if germ line mutation Comments Gatekeepers p53 Transcription factor Li-Fraumeni syndrome Also mutated in 50% of human cancers Rb1 Transcriptional regulator Familial retinoblastoma Often mutated in other cancers APC Regulates βcatenin function Familial adenomatus polyposis Often mutated in sporadic colorectal cancers BRCA1 DNA repair Breast and ovarian cancer Rarely mutated in sporadic breast cancers BRCA2 DNA repair Breast cancer(female and male) MSH2 MLH1 DNA mismatch repair Hereditary nonpolyposis colorectal cancer Caretakers Mutation permits further mutations
  8. 8. 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 (non-inherited), remaining ones are familial
  9. 9. 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.
  10. 10. The “two-hit" origin of retinoblastoma
  11. 11. p53 Gene  Situated at the short arm of the chromosome 1  It is also called TP53 or tumor protein codes for protein that regulate the cell cycle  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 Apoptosis cell death if there is extensive DNA damage
  12. 12. 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”.
  13. 13. P53 gene  Involved directly in DNA repair  Transcriptional target gene p53R2 encodes ribonucleotide reductase important for DNA replication & repair  Interacts with AP endonuclease & DNA polymerase
  14. 14. MECHANISM OF P53
  15. 15. 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
  16. 16. Role of p53 in cells with damaged DNA
  17. 17. Li- Fraumeni syndrome  Li- Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome.  This means that a person who has LFS will have an increased risk of developing cancer.
  18. 18. Li- Fraumeni syndrome  Common type of cancer found in LFS- bone cancer,breast cancer, brain cancer  Affected individuals Carry germ line mutation in one p53 allele, but tumors display mutation at both alleles  Another example of two-hit hypothesis
  19. 19. APC Gene  Implicated in familial adenomatous polyposis coli and most sporadic colorectal cancers  β-catenin- is a dual function protein, tissue formation & helps to control the acticity(expression) of other gene & promote cell growth & division.  In humans, β-catenin is encoded by the CTNNB1 gene
  20. 20. APC Gene  Excess of β-catenin promotes uncontrolled growth & division of cells  APC binds to and inhibits the function of β-catenin  Mutant APC is unable bind β-catenin to down regulate its activity & produce desmoid tumor
  21. 21. WT-1 gene  WT1(Wilms tumor 1)gene codes for protein responsible development of the kidney and gonads  It codes for a DNA-binding protein that represses transcription of PDGF and IGF-I which promotes growth
  22. 22. WT-1 gene  WT1 protein regulates the activity of other genes by binding to specific regions of DNA that is why it is also called transcription factor  It also causes self-destruction of cells (apoptosis)  Loss of WT-1 gene expression also occur in many breast cancers
  23. 23. NF-1 gene  Germ line mutation in type 1 neurofibromatosis (NF)  Encode neurofibromin, a negative regulator of ras gene  Inactivation of NF-1 permits unopposed ras, thereby promotes cell growth
  24. 24. 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
  25. 25. BRCA1 and BRCA2 genes  Breast (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
  26. 26. Conclusion  suppression of genes that are essential for the continuing of the cell cycle.  If the damage cannot be repaired, promote apoptosis.  Produce protein responsible for inhibition of metastasis  Inactivation of tumour suppressor gene causes tumour
  27. 27. References  www.bioinformatics.org/p53/introduction.html.  www.ncbi.nlm.nih.gov/podmed/12060387  www.nlm.nih.gov/geneAPC  www.nlm.nih.gov/gene/NF1  www.wikipedia.org/wiki/Neoplasm