p53 plays a major role in preventing tumour development. It responds to a range of potentially oncogenic stresses by activating protective mechanisms, most notably cell cycle arrest and apoptosis. Its importance as a tumour suppressor is reflected by its high rate of mutation in human cancer, with >50% of adult human tumours bearing inactivating mutations or deletions in the TP53 gene. In many cancers where p53 is wild-type, the p53 pathway may be altered by other oncogenic events. This means that the p53 response is probably defective in most cancers.

Pilot screening programme for small molecule activators of p53
Rachel G. Berkson, Jonathan J. Hollick, Nicholas J. Westwood, Julie A. Woods, David P. Lane, Sonia Lain
Int J Cancer. 2005 Feb 23

The p53 gene is located on chromosome 17 (17p13). There are 11 exons. There is a very large intron between exons 1 and 2. Exon 1 is non-coding in the human p53 and it has been demonstrated that this region could form a stable stem-loop structure which binds tightly to wild type p53 but not to mutant p53.

The human p53 protein comprises of several domains:

1. The amino-terminus part (1-44) contains the transactivation domain, which is responsible for activating downstream target genes.

2. A proline-rich domain (58-101) mediates p53 response to DNA damage through apoptosis.

3. The DNA-binding domain (102-292) is a core domain which consists of a variety of structural motifs. It is the target of 90% of p53 mutations found in human cancers as a single mutation within this domain can cause a major conformational change.

4. The oligomerization domain (325-356) consists of a β-strand, which interacts with another p53 monomer to form a dimer, followed by an α-helix which mediates the dimerization of two p53 dimers to form a tetramer.

5. Three putative nuclear localization signals (NLS) have been identified in the C-terminus, through sequence similarity and mutagenesis. The most N-terminal NLS (NLSI), which consists of 3 consecutive Lysine residues to a basic core, is the most active and conserved domain.

6. Two putative nuclear export signals (NES) have been identified. The leucine-rich C-terminal NES, found within the oligomerization domain, is highly conserved and it has been suggested that oligomerization can result in masking of the NES, resulting in p53 nuclear retention.

Inactivation of the p53 gene is essentially due to small mutations (missense and nonsense mutations or insertions/deletions of several nucleotides), which lead to either expression of a mutant protein (90% of cases) or absence of a protein (10% of cases. Mutations of p53 have been found in nearly all tumor types and are estimated to contribute to around 50% of all cancers.

The role of natural p53 variants (polymorphisms) or variants in the p53 signalling pathway is an area that is less well explored. Several polymorphisms have been identified in the p53 gene. A well known SNP occurs on Codon 72 (Arg/Pro).

p53 transcription under different conditions is related to vast number of biological events in response to various cellular stresses. Human p53 consists of two promoters:

• P1 responsible for the transcription of the major p53 mRNA species and located upstream of first exon,
• P2 involved in transcription of other rarer species and located within the first intron region.

Recent studies have suggested that there is another "P2" located within intron 4 and responsible generating the p53 isoforms.

Regulatory elements are found in both p53 upstream and downstream of start sites including exons and introns. So far, there are more than 15 transcription factors binding sites are experimentally and computationally identified within the P1 and first exon regions.

A binding site for members of the PAX family of transcription factors was identified in the first non-coding exon of the human p53 gene. c-Myc/Max heterodimers have been shown to bind to and transactivate the human promoter through a CATGTG motif. NF-kB Jun/Fos and homeobox factor Hoxa5 are shown to regulate p53 expression transcriptionally. These transcription factors function under different biological conditions such as apoptosis, cell-cycle arrest and etc, in terms of time, space and quantity.

Post-translational modifications and activation of p53 by genotoxic stresses
Appella, E. and Anderson, C.W.
Eur. J. Biochem. 268, 27644-72 (2001)

The p53 protein is a potent antigen that has the ability to raise antibodies when injected into a foreign host. Currently, the p53 knowledgebase contains more than 50 distinct antibodies recognizing the different domains of p53. Most of the antibodies recognize epitopes localized in the N-terminal of p53. Some of the antibodies are able to bind to p53 in its native conformation, while other antibodies, like pAb240, DO12 and HO3.5, can only bind to mutant p53 whose structural conformation has been altered.