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

Occurrence of p53 mutations in human cancers

Greenblatt et al. (1995) Cancer Res. 54:4855

Lung (897) 56% Adrenal (31) 23% Colon (960) 50% Breast (1536) 22% Esophagus (279) 45% Endometrium (224) 22% Ovary (386) 44% Mesothelioma (23) 22% Pancreas (170) 44% Renal (102) 19% Skin (220) 44% Thyroid (299) 13% Gastric (314) 41% He matological (1916) 12% He ad & neck (524) 37% Carcinoid (13) 11% Bladder (308) 34% Melanoma (70) 9% Sarc oma (339) 31% Parathyroid (13) 8% Prostate (87) 30% Cevix (350) 7% He patoce llular (716) 29% Neuroblastoma (212) 1% Brain (456) 25% others (155) 0%

Tumor type (n) p53 mutation Tumor ty pe ( n)

p53 mutation

All tumors: 37%50%

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:• 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

http://www.kcl.ac.uk/kis/schools/life_sciences/life_sci/nikolovaR.html

Unbound p53 p53 bound to DNA

p53 binds DNA as a tetramer,

upstream of target genes

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

Courtesy of Dr. Bob Duronio http://www.rockefeller.edu/pubinfo/p53part2.html

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-/-

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