The document summarizes information about p53, a tumor suppressor protein. It discusses the history and discovery of p53, its structure and domains, mechanisms of stability and activation in response to stress. It also describes p53's key functions in cell cycle arrest and apoptosis. The document notes common mutations in p53 in different cancer types and potential therapeutic applications targeting p53 pathways.

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

4. STRUCTURE

5. AMINO TERMINAL DOMAIN
 transactivation
 transcription factors – MDM2
PROLINE-RICH REGION
 stability
CENTRAL CORE
 DNA binding domain
C-TERMINAL DOMAIN
 negative regulation

6. STABILITY OF P53

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

11. APOPTOSIS

13. MUTATIONS

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.