p53 is a nuclear phospho-protein which, in response to DNA damage, slows progression through the cell cycle and initiates apoptosis if damage is severe.

Structure

The core domain structure consist of a beta-sandwich that serves as a scaffold for two large loops and a loop-sheet-helix motif. The two loops, which are held together in part by a tetrahedrally coordinated zinc atom, and the loop-sheet-helix motif form the DNA binding surface of p53. Residues from the loop-sheet-helix motif interact in the major groove of the DNA, while an arginine from one of the two large loops interacts in the minor groove.

The loops and the loop-sheet-helix motif consist of the conserved regions of the core domain and contain the majority of the p53 mutations identified in tumors.

Pathology

 germline mutations in Li-Fraumeni syndrome (MIM.151623)
 somatic mutations in tumors

• Inactivation of the tumour suppressor p53 by mutations is the most common defect in cancer cells. The majority of the mutations occur in the core domain which contains the sequence-specific DNA binding activity of the p53 protein (residues 102-292), and they result in loss of DNA binding.
• Tumour-specific point mutations occur in many forms of human cancer with as many as 50% of cancers containing a p53 mutation. 20% of mutations are concentrated at 5 'hot-spot' codons.

 inactivation of p53 protein by HPV-E6 and HPV-E7 oncoproteins

Features

 p53-inducible genes (p21, Bax, etc...)
 p53 acetylation
 p53 pathway

References

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 Smith J. Human Sir2 and the 'silencing' of p53 activity. Trends Cell Biol. 2002 Sep;12(9):404-6. PMID: #12220851#

 Lane DP, Lain S. Therapeutic exploitation of the p53 pathway. Trends Mol Med. 2002;8(4 Suppl):S38-42. PMID: #11927286#

 Lohrum MA, Vousden KH. Regulation and function of the p53-related proteins: same family, different rules. Trends Cell Biol. 2000 May;10(5):197-202. PMID: #10754563#

 Hartmann A, Blaszyk H, Kovach JS, Sommer SS. The molecular epidemiology of p53 gene mutations in human breast cancer. Trends Genet. 1997 Jan;13(1):27-33. PMID: #9009845#

 Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997 Feb 7;88(3):323-31. PMID: #9039259#