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

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 http://ghr.nlm.nih.gov/gene=tp53

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

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

p53 structure The p53 gene has 3 functional domains: http://www.kcl.ac.uk/kis/schools/life_sciences/life_sci/nikolovaR.html The p53 gene has 3 functional domains: N-terminal: contains transcription activation signal C-terminal: controls oligomerization Central area (aa 100-300): DNA binding site, contains transcription activation signal Most commonly mutated area in cancer is this central DNA-binding area

p53 binds DNA as a tetramer, upstream of target genes Unbound p53 p53 bound to DNA http://www.rcsb.org/pdb/molecules/pdb31_1.html

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

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

p53 is involved in a mutual feedback system with its E3 ubiquitin ligase mdm2 http://www.rockefeller.edu/pubinfo/p53part2.html Courtesy of Dr. Bob Duronio

p53-mediated cell cycle arrest versus apoptosis http://www.hcoa.org/newsite/FacultyandStaff/xiangwei_wu.asp

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

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

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

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