2. Learning Outcomes
• What is p53 gene
• What are its functions
• How it regulates cell cycle
• What happens if p53 is inactivated
• How p53 is inactivated
• What are the cancers associated with p53 mutation
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3. P53 Gene
• This is a tumor suppressor gene ( its activity stops the
formation of tumors)
• Located on 17p13, first discovered in 1979
• The p53 protein is the product of p53 gene
• P-protein
• 53- weight of the protein, 53 kDa
• Located in almost all normal tissues
• Unstable and degrades very quickly
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4. • Is one of the most commonly mutated gene in cancer
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5. Function
• Regulation of Cell cycle
• DNA repair
• Apoptosis
• Prevents neoplastic transformation either by cell cycle arrest or by
triggering apoptosis.
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7. DNA Damage Increased p53 levels
Prevent Cell from entering S
phase of cell cycle
Allows time for the DNA repair to
take place
DNA Not Repaired
Apoptosis
GUARDIAN OF
THE GENOME
Conserves stability
Triggers expression of
p53 gene
Arrest of cell cycle at
G1 Phase
DNA Repaired
P53 degrades
Cell cycle continues
Permanent
arrest/senescence
P53 induces
DNA repair
genes
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10. • P53 is the transcriptional regulator of one of the genes named WAF
1
• Resulting in increased WAF proteins named as p 21
• P21 blocks CDK4/CyclinD complex ….. Cell cycle is halted in G1 stage
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13. Regulation of p53 protein
Normal cells … p53 is very unstable
p53 Mdm2 Gene
mdm2 protein
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14. Regulation of p53 protein
Normal cells
p53
mdm2 protein
P53 mdm2
complex
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15. Regulation of p53 protein
Normal cells
p53
P53 mdm2
complex
Degradation
Ubiquitin
mediated mdm2 proteinDegraded p53
plus
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16. Regulation of p53 protein
Cells with damaged DNA
NO P53 mdm2
complex
No Degradation
p53 P
mdm2 protein
Increased p53 levels
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17. What happens when p53 is inactivated?
DNA damage
No p53/
inactivated
p53
Cell cycle
progresses with
damaged DNA
No cell cycle
arrest Neoplastic
transformation
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18. How p53 is inactivated??
• Mutations
• Heterozygous and homozygous loss of alleles
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19. What are the cancers associated with p53
mutations??
• Most human cancers!
• MC breast, colorectal, liver, lung, and ovarian cancers.
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20. Summary
• What is p53 gene
• What are its functions
• How it regulates cell cycle
• What happens if p53 is inactivated
• How p53 is inactivated
• What are the cancers associated with p53 mutation
www.ilovepathology.com