1. The guardian of the genome
p53
The guardian of the genome
By Siddhartha Ray

2. p53: general info 393 amino acids long Localized to the nucleus
Found at locus 17p13.1
About 200 germline TP53
mutations have been discovered
One of a highly conserved gene
family that also includes p63
and p73
However the other genes lack
p53’s tumor suppressor abilities

3. Greenblatt et al. (1995) Cancer Res. 54:4855
Occurrence of p53 mutations in human cancers
50%
Greenblatt et al. (1995) Cancer Res. 54:4855

4. Li-Fraumeni Syndrome (LFS)
Rare autosomal dominant predisposition to certain types of cancer
LFS has only been diagnosed in about 300 families wordwide
It has been estimated that roughly half of LFS cases involve a p53 mutation
Courtesy of Dr. Bob Duronio

5. p53 structure The p53 gene has 3 functional domains:
The p53 gene has 3 functional domains:
N-terminal: contains transcription activation signal
C-terminal: controls oligomerization
Central area (aa ): DNA binding site, contains transcription activation signal
Most commonly mutated area in cancer is this central DNA-binding area

6. p53 binds DNA as a tetramer, upstream of target genes
Unbound p53
p53 bound to DNA

7. There are 3 methods of activating the p53 pathway and 3 potential results
Guimaraes et Hainut (2002) Biochimie 84:83

8. Protein interactions in the p53 pathway
Guimaraes et Hainut (2002) Biochimie 84:83

9. p53 is involved in a mutual feedback system with its E3 ubiquitin ligase mdm2
Courtesy of Dr. Bob Duronio

10. p53-mediated cell cycle arrest versus apoptosis

11. p53 knockout mouse
p53 knockout mice were bred in 1992 by Donehower et al.

12. P53/mdm2 double knockout Bred in 1995 by Jones et. al p53 -/- mdm2-/-
Courtesy of Dr. Bob Duronio

13. 3 types of mutations
Guimaraes et Hainut (2002) Biochimie 84:83

14. Late vs early acting mutations
Guimaraes et Hainut (2002) Biochimie 84:83