In humans, the p53 protein is encoded by the TP53 gene located on the short arm of chromosome 17, more precisely at 17p13.1. The gene spans more than 20 kb (20,000 bases) with a non-coding exon 1 and a very long first intron of 10 kb. The coding sequence stretches from exon 2 to the initial part of exon 11.
The human p53 protein can be divided into domains, each corresponding to specific functions:
- The amino-terminus region (amino acids 1-42) contains the acidic transactivation domain and the mdm2 protein binding site.
- The region that corresponds to amino acids 40-92 contains a series of repeated proline amino acids, as well as a second transactivation domain.
- The central region (amino acids 101-306) allows for binding to DNA in the regulatory regions of target genes. It is the target of 90% of TP53 mutations found in human cancers.
- The carboxy-terminus contains a series of nuclear localization sequences and an oligomerization domain (307-355), which participates in dimer and tetramer formation. It is the tetramer that is active in transcriptional regulation.
Deletion of one allele in the short arm of chromosome 17 and a functionally inactivating mutation of the other allele at the specific location are among the most common genetic abnormalities documented in human cancers. Inactivation of TP53 is essentially due to mutations (missense and nonsense mutations or insertions/deletions of one or several nucleotides), which lead to either expression of a mutant protein (90% of cases) or absence of protein (10% of cases). Wild-type p53 protein has a short half-life, and the level present in the nucleus of normal cells is below the sensitivity of immunohistochemical (IHC) detection. Mutations in TP53 result in a protein with a prolonged half-life that then accumulates in the nucleus and can be detected by IHC. Immunostaining for p53 protein has been proposed as an indirect method of detecting a TP53 mutation
These images show the p53 protein immunostaining pattern. The left side shows adrenocortical tumor tissue with negative nuclear immunostaining. The right side shows adrenocortical tumor tissue with the R337H TP53 mutation and nuclear positivity for p53 protein.
Several polymorphisms have been identified in the TP53 gene. Some of them have been analyzed on a large scale; therefore, their distribution in the human population is well known and includes the polymorphism at codon 72 that could code for proline or arginine, as well as the polymorphism that encodes the duplication of 16 bp in intron 3 and several others. Other polymorphisms have been rarely described, and their significance remains to be analyzed. Analysis of these single-nucleotide polymorphisms and microsatellite markers could help us construct the TP53 haplotype. See the picture above to better understand TP53 structure.
Coding regions are represented by squares 2 to 11. The amino acids (residues) are represented by 1 to 393. Evolutionary conserved regions are represented by I to V.