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Tumor suppressorgenes

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for Undergraduate Medical Students (MBBS)

Publicada em: Saúde e medicina
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Tumor suppressorgenes

  1. 1. Molecular Biology of Cancer -Molecular Biology of Cancer - Tumor suppressor genesTumor suppressor genes Dr.CSBR.Prasad, M.D.,
  2. 2. Failure of growth inhibition is one of the fundamental alterations in the process of carcinogenesis
  3. 3. • Oncogenes drive the proliferation of cells, the products of tumor suppressor genes apply brakes to cell proliferation • The tumor suppressor proteins form a network of checkpoints that prevent uncontrolled growth • Eg: RB and p53 – They are part of a regulatory network that recognizes genotoxic stress from any source, and responds by shutting down proliferation
  4. 4. Tumor suppressor gene Oncogene
  5. 5. The tumor suppressor proteins form a network of checkpoints that prevent uncontrolled growth
  6. 6. Oncogene expression in an otherwise normal cell leads to ……. Expression of an oncogene in an otherwise completely normal cell leads to quiescence, or to permanent cell cycle arrest (oncogene- induced senescence), rather than uncontrolled proliferation
  7. 7. In this class we will deal with… • Tumor suppressor genes, their products, and • Mechanisms by which loss of their function contributes to unregulated cell growth • The protein products of tumor suppressor genes: – Transcription factors – Cell cycle inhibitors – Signal transduction molecules – Cell surface receptors, and – Regulators of cellular responses to DNA damage
  8. 8. Selected Tumor Suppressor Genes Involved in Human Neoplasms
  9. 9. Tumor suppressor genes • Physiologically they regulate cell growth • It is a misnomer • Failure of growth inhibition is key event in carcinogenesis • Loss of function of these genes - tumor • The proteins that apply break to cell proliferation are the products of these genes
  10. 10. Tumor suppressor genes • Genes act by coding for growth controlling molecules or growth factors • Two pathways – Control over mitosis – Control over biochemical processes in the cell that govern growth and differentiation i.e., gene expression
  11. 11. Protein products of tumor suppressor genes • Cell cycle control • Regulation of apoptosis • Activities of cell survival and growth
  12. 12. Protein products of tumor suppressor genes-function • Transcription factors • Cell cycle inhibitors • Signal transduction factors • Cell surface receptors • Regulators of cellular response to DNA damage
  13. 13. Tumor suppressor genes • RB gene / retinoblastoma gene • p53 gene • APC gene/adenomatous polyposis coli gene • B cell lymphoma gene/bcl 2 gene • WT 1 gene/Wilms tumor gene • NF1/NF2,Neurofibromatosis gene
  14. 14. Selected Tumor Suppressor Genes Involved in Human Neoplasms
  15. 15. RB gene- two hit hypothesis • Located on 13q14 • Both normal alleles must be inactivated (2- hits) – First hit: Familial cases-born with one defective copy of gene – Second hit: The second intact copy undergoes somatic mutation • Sporadic cases-both normal RB alleles are lost by somatic mutation in one of the retinoblasts
  16. 16. RB Gene • Familial RB show increased risk for osteosarcoma & soft tissue sarcomas • RB locus is seen in adenocarcinomas of breast, small cell ca lung & bladder ca • Alterations in “RB pathway” involving INK4a, CDK’s, RB proteins are present in cancer cells
  17. 17. LOH- Loss of heterozygosity • Child carrying inheritent mutant RB allele in all somatic cells is perfectly normal, except for increased risk for RB • Child is heterozygous for the RB gene, which does not affect cell behavior • Cancer develops when cell becomes homozygous for mutant allele
  18. 18. LOH- Loss of heterozygosity • The cell loses heterozygosity for normal RB gene (i.e., loss of heterozygosity)
  19. 19. Pathogenesis of Retinoblastoma
  20. 20. Pathogenesis of Retinoblastoma
  21. 21. Pathogenesis of Retinoblastoma
  22. 22. RB protein • Nuclear phosphoprotein, regulates cell cycle • Active hypophosphorylated state in quiescent cells • Inactive hyperphophorylated state in G1/S cell cycle transition
  23. 23. RB gene • Regulates advancement of cells from G1/S phase of cell cycle • With RB mutation- transcription factor regulation is lost- persistent cell cycling • TGF b is a growth inhibiting cytokine that upregulates CDK inhibitors, preventing hyperphosphorylation
  24. 24. p53
  25. 25. p53 gene • Normal function- prevent propogation of genetically damaged cells • When DNA is damaged-p53 upregulation- transcription of genes that arrest cell cycle and repair DNA • Cell cycle arrest is mediated by p53 dependent transcription CDK inhibitor p21 • If DNA cannot be repaired, p53 induces apoptosis
  26. 26. Li-fraumeni syndrome • High risk of developing carcinoma by inactivation of 2 nd normal allele of somatic cells • Leukemia, sarcoma, breast cancer, brain tumor • Homozygous loss of p53-DNA damage goes Unrepaired-many mutant genes-cancer
  27. 27. Li-fraumeni syndrome
  28. 28. APC / ß catenin
  29. 29. APC gene/ ß catenine pathway • Develop thousands of adenomatous polyps • APC protein binds and regulates the degradation of b catenine levels in cytoplasm • Absence of APC protein-b catenine levels increase- translocate to nucleus-up regulate cell proliferation • APC is a negative regulator of b catenine
  30. 30. Multiple adenomas
  31. 31. TGFß pathway • Up regulate growth inhibitory genes • Colon cancers, gastric ca in HNPCC Mutated TGF ß • receptors prevent growth restraining effects
  32. 32. TGFß pathway
  33. 33. NF1 gene • Regulates signal transduction by RAS pathway • Homozygous loss impairs conversion of active RAS to inactive RAS • Germ line inheritance of one mutant allele predipose to multiple NF • Loss of 2 nd NF gene - progression to malignancy
  34. 34. RAS pathway
  35. 35. WT -1 gene • WT-1 protein transcriptional activator of genes involved in renal and gonadal differentiation • Tumorigenic function - role in differentiation of genitourinary tissues • Wilms’ tumor of kidney
  36. 36. Evasion of Apoptosis BCL-2, p53, MYC
  37. 37. • Genes inhibiting apoptosis –BCL2,BCL-XL • Genes promoting apoptosis –BAD, BAX, BID • t(14;18) in follicular lymphoma – over expression of BCL2
  38. 38. Defects in DNA repair • Mismatch repair (HNPCC syndrome) • Nucleotide excision repair (Xero. Pigmentosa) • Recombination repair (Ataxia telangiectasia, Fanconi’s anemia & Bloom syndrome) • Mutations not repaired in defects – Genomic instability syndrome – Cancer Self sufficiency in growth signals Insensitivity to growth inhibitory signals Evasion of apoptosis Defects in DNA repair Limitless replicative potential Sustained angiogenesis Ability to invade and metastasis
  39. 39. Bloom’s syndrome, Xeroderma pigmentosum
  40. 40. Ataxia telangiectasia
  41. 41. HNPCC Hereditary nonpolyposis colon ca syndrome • Born with one defective copy of one of several DNA repair genes involved in mismatch repair (MSH2 & MLH1) • Loss of normal spell checker function • Microsatellite repeats • Variation in microsatellite – instability • Hall mark of mismatch repair defects
  42. 42. Xeroderma pigmentosum • UV light induces mutagenic - pyrimidine dimers – defect of nucleotide excision repair • Develop skin cancer
  43. 43. BRCA-1 and BRCA-2 • Involved in repair of double stranded DNA breaks by homologous recombination • Familial breast cancers, ovarian ca, melanoma, pancreatic ca
  44. 44. Defects in DNA repair Self sufficiency in growth signals Insensitivity to growth inhibitory signals Evasion of apoptosis Defects in DNA repair Limitless replicative potential Sustained angiogenesis Ability to invade and metastasis
  45. 45. Limitless Replicative Potential
  46. 46. Limitless replicative potential teleromerase • Telomerase not active in somatic cells • Cellular telomerase progressively shorten with each cell cycle - replicative senescence • Cancer cells reactivate telomerase • 90 % of human tumors show telomerase activity
  47. 47. E N D