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p53
THE TUMOR
SUPPRESSOR


   Presented by
 Spoorthi shridhar
 MSc. biochemistry
INTRODUCTION
•   Tumor Suppressor

•   53 kDa protein

•   Encoded by TP53 gene

•   Regulates cell cycle
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
STRUCTURE
AMINO TERMINAL DOMAIN
 transactivation

 transcription factors – MDM2



 PROLINE-RICH REGION
 stability



 CENTRAL CORE
 DNA binding domain



 C-TERMINAL DOMAIN
 negative regulation
STABILITY OF P53
ACTIVATION
 PHYSICAL AGENTS:
 UV, gamma, X-rays



CHEMICAL AGENTS:
 carcinogens

 chemotherapeutic agents

 alkylating agents



OTHER CAUSES
 hypoxia

 heat shock
FUNCTIONS
   activation in response to stress stimuli

  prevents inappropriate cell proliferation:
 cell cycle arrest
 apoptosis
CELL CYCLE ARREST IN G1 PHASE




                 Molecular Biology Of The Cell
                                 Bruce Alberts
CELL CYCLE ARREST IN G2 PHASE
              p53

           Gadd 45

             CDK1

         Cyclin B/CDK1

     Prevents phosphorylation
APOPTOSIS
MUTATIONS
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 273

UV AND SKIN CANCERS:

•   CC to TT transitions
•   Codons 245 and 247/248

COLORECTAL CANCER:

•   34% proximal colon tumors
•   45% distal colon and rectal tumors
Molecular Cell Biology
          Lodish Et al.
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
•   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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p53

  • 1. p53 THE TUMOR SUPPRESSOR Presented by Spoorthi shridhar MSc. biochemistry
  • 2. INTRODUCTION • Tumor Suppressor • 53 kDa protein • Encoded by TP53 gene • Regulates cell cycle
  • 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
  • 5. AMINO TERMINAL DOMAIN  transactivation  transcription factors – MDM2 PROLINE-RICH REGION  stability CENTRAL CORE  DNA binding domain C-TERMINAL DOMAIN  negative regulation
  • 7. ACTIVATION PHYSICAL AGENTS:  UV, gamma, X-rays CHEMICAL AGENTS:  carcinogens  chemotherapeutic agents  alkylating agents OTHER CAUSES  hypoxia  heat shock
  • 8. FUNCTIONS  activation in response to stress stimuli  prevents inappropriate cell proliferation:  cell cycle arrest  apoptosis
  • 9. CELL CYCLE ARREST IN G1 PHASE Molecular Biology Of The Cell Bruce Alberts
  • 10. CELL CYCLE ARREST IN G2 PHASE p53 Gadd 45 CDK1 Cyclin B/CDK1 Prevents phosphorylation
  • 12.
  • 14. 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 273 UV AND SKIN CANCERS: • CC to TT transitions • Codons 245 and 247/248 COLORECTAL CANCER: • 34% proximal colon tumors • 45% distal colon and rectal tumors
  • 15. Molecular Cell Biology Lodish Et al.
  • 16. 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
  • 17. 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.