p53

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p53

  1. 1. p53THE TUMORSUPPRESSOR Presented by Spoorthi shridhar MSc. biochemistry
  2. 2. INTRODUCTION• Tumor Suppressor• 53 kDa protein• Encoded by TP53 gene• Regulates cell cycle
  3. 3. HISTORY• 1979 - David Lane and Lionel Crawford• 1983 - The term “p53” was coined• p53 acknowledged as an oncogene• 1984 - David Wolf and Rotter• 1989 - p53 tagged as a tumor suppressor
  4. 4. STRUCTURE
  5. 5. AMINO TERMINAL DOMAIN transactivation transcription factors – MDM2 PROLINE-RICH REGION stability CENTRAL CORE DNA binding domain C-TERMINAL DOMAIN negative regulation
  6. 6. STABILITY OF P53
  7. 7. ACTIVATION PHYSICAL AGENTS: UV, gamma, X-raysCHEMICAL AGENTS: carcinogens chemotherapeutic agents alkylating agentsOTHER CAUSES hypoxia heat shock
  8. 8. FUNCTIONS activation in response to stress stimuli prevents inappropriate cell proliferation: cell cycle arrest apoptosis
  9. 9. CELL CYCLE ARREST IN G1 PHASE Molecular Biology Of The Cell Bruce Alberts
  10. 10. CELL CYCLE ARREST IN G2 PHASE p53 Gadd 45 CDK1 Cyclin B/CDK1 Prevents phosphorylation
  11. 11. APOPTOSIS
  12. 12. MUTATIONS
  13. 13. LUNG CANCER:• 33% in adenocarcinomas to 70% in small cell lung cancers• GC to TA transversions• Exogenous carcinogens such as benzopyrene• Codons 157, 248 and 273UV AND SKIN CANCERS:• CC to TT transitions• Codons 245 and 247/248COLORECTAL CANCER:• 34% proximal colon tumors• 45% distal colon and rectal tumors
  14. 14. Molecular Cell Biology Lodish Et al.
  15. 15. THERAPEUTIC APPLICATIONS• Inhibiting interaction of MDM2 with p53• Small molecule inhibitors: nutlins• Antisense oligodeoxy nucleotides• Inhibiting E6 protein of Human Papilloma Virus• Leptomycin B and Actinomycin D
  16. 16. • Induction of apoptotic pathways• Introduction of wt p53 gene into tumors GENE THERAPY:• 2004 - treatment of head and neck cancer in China• McCormick and co-workers, USA - infection of the tumor with recombinant adenovirus.

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