p53
description
Transcript of p53
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p53
The guardian of the genome
By Siddhartha Ray
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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
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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%
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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
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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
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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
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There are 3 methods of activating the p53 pathway
and 3 potential results
Guimaraes et Hainut (2002) Biochimie 84:83
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Protein interactions in the p53 pathway
Guimaraes et Hainut (2002) Biochimie 84:83
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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
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p53-mediated cell cycle arrest versus apoptosis
http://www.hcoa.org/newsite/FacultyandStaff/xiangwei_wu.asp
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p53 knockout mouse
• p53 knockout mice were bred in 1992 by Donehower et al.
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P53/mdm2 double knockout
• Bred in 1995 by Jones et. al
p53 -/-mdm2-/-
p53-/- mdm2-/-Courtesy of Dr. Bob Duronio
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3 types of mutations
Guimaraes et Hainut (2002) Biochimie 84:83
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Late vs early acting mutations
Guimaraes et Hainut (2002) Biochimie 84:83