While there are numerous isoforms for p53 and the associated p53 family members (p73 and p63), their functional importance is a mystery. p53 Isoforms are generated by alternative splicing, alternative translation initiation sites, and different promoter usage.
It is believed that full-length p53 and its isoforms would be able to interact to exert some amount of control on the p53 activity. It has been demonstrated that isoforms’ differential ratios could produce distinctive responses to stresses and affect oncogenesis in a clear way.
In one study, it was observed that urinary bladder tumors were caused by the expression of an N-terminally truncated p53 known as p44. In addition, breast tumors were found to have variable expression of p53 isoforms when compared with normal breast tissue1.
Structure of p53 proteins
This protein is active as a tetramer of 4 chains of 393 amino acids, with each chain having a number of domains. At the N-terminal, there are:
- two distinct transactivation domains (TADI and TADII)
- a nuclear export signal (NES)
- the proline rich domain (PD)
- the DNA binding domain (DBD)
At the C-terminus, there are:
- an oligomerization domain (OD)
- a second NES
- three nuclear localization signals (NLS)
- a lysine rich regulatory domain (RD)
For p53’s regulation, both TADI (residues 1-42) and TADII (residues 43-62) are vital as they provide binding sites for the negative regulator MDM2 and the transcriptional machinery – these play different roles in the activation of a distinct group of p53 target genes.
While the precise function of the PD (residues 63-97) is yet to be fully understood, the high proline frequency is preserved though the species. Moreover, based on studies using mouse models, the length of the PD is also known to be important to preserve the tumor suppressive function of the p53 protein. Within the domain, a common SNP (single nucleotide polymorphism) at codon 72 is present which further emphasizes the importance of this region.
In addition, the DBD (residues 102-292) is crucial for the p53 transcriptional activity and includes 4 of the 5 conserved boxes in the p53 protein. With the help of the OD (residues 323-356), the p53 forms a tetramer which is arranged as a dimer of dimers.
A cluster of three NLSs are present in the C-terminus of p53 which mediate the protein’s nuclear location. After binding to specific receptors, these sequences enable selective passage of the p53 protein via the nuclear pore complex.
It has been shown that the highly conserved region – C-terminal NES – is crucial for nuclear export of p53 proteins. For nuclear-cytosolic shuttling of p53, both the NES and NLS regions are needed to regulate the transcriptional function of p53 proteins2, 3.
Figure 1. p53 functional domains
- Levine AJ, Oren M. 2009. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 9(10):749-58. doi: 10.1038/nrc2723.
- Nag S, Qin J, Srivenugopal KS, Wang M, Zhang R. 2013. The MDM2-p53 pathway revisited. J Biomed Res. 27(4):254-71. doi: 10.7555/JBR.27.20130030.
- Meek DW, Anderson CW. 2009. Posttranslational modification of p53: cooperative integrators of function. Cold Spring Harb Perspect Biol. 1(6):a000950. doi:10.1101/cshperspect.a000950.
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