P53
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p53 gene: The Guardian of the genome. functions, regulation and inactivation
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P53
- 1. TUMOR SUPPRESSOR GENES p53 GENE www.ilovepathology.com
- 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 www.ilovepathology.com
- 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 www.ilovepathology.com
- 4. • Is one of the most commonly mutated gene in cancer www.ilovepathology.com
- 5. Function • Regulation of Cell cycle • DNA repair • Apoptosis • Prevents neoplastic transformation either by cell cycle arrest or by triggering apoptosis. www.ilovepathology.com
- 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 www.ilovepathology.com
- 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 www.ilovepathology.com
- 12. Regulation of p53 protein www.ilovepathology.com
- 13. Regulation of p53 protein Normal cells … p53 is very unstable p53 Mdm2 Gene mdm2 protein www.ilovepathology.com
- 14. Regulation of p53 protein Normal cells p53 mdm2 protein P53 mdm2 complex www.ilovepathology.com
- 15. Regulation of p53 protein Normal cells p53 P53 mdm2 complex Degradation Ubiquitin mediated mdm2 proteinDegraded p53 plus www.ilovepathology.com
- 16. Regulation of p53 protein Cells with damaged DNA NO P53 mdm2 complex No Degradation p53 P mdm2 protein Increased p53 levels www.ilovepathology.com
- 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 www.ilovepathology.com
- 18. How p53 is inactivated?? • Mutations • Heterozygous and homozygous loss of alleles www.ilovepathology.com
- 19. What are the cancers associated with p53 mutations?? • Most human cancers! • MC breast, colorectal, liver, lung, and ovarian cancers. www.ilovepathology.com
- 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