Mutant TP53 posttranslational modifications: challenges and opportunities

Abstract

The wild-type (WT) human p53 (TP53) tumor suppressor can be posttranslationally modified at over 60 of its 393 residues. These modifications contribute to changes in TP53 stability and in its activity as a transcription factor in response to a wide variety of intrinsic and extrinsic stresses in part through regulation of protein-protein and protein-DNA interactions. The TP53 gene frequently is mutated in cancers, and in contrast to most other tumor suppressors, the mutations are mostly missense often resulting in the accumulation of mutant (MUT) protein, which may have novel or altered functions. Most MUT TP53s can be posttranslationally modified at the same residues as in WT TP53. Strikingly, however, codons for modified residues are rarely mutated in human tumors, suggesting that TP53 modifications are not essential for tumor suppression activity. Nevertheless, these modifications might alter MUT TP53 activity and contribute to a gain-of-function leading to increased metastasis and tumor progression. Furthermore, many of the signal transduction pathways that result in TP53 modifications are altered or disrupted in cancers. Understanding the signaling pathways that result in TP53 modification and the functions of these modifications in both WT TP53 and its many MUT forms may contribute to more effective cancer therapies.

Keywords: TP53; acetylation; methylation; p53; phosphorylation; transcription; ubiquitylation.

Figure 1

Cancer-related signaling to WT and MUT TP53. A wide variety of stress stimuli activate cellular signaling pathways leading to PTMs of TP53 and many of its interacting partners, resulting in the activation and stabilization of WT TP53. WT TP53 functions as a transcription factor to activate or repress hundreds of target genes; it also has non-transcriptional functions that are primarily cytoplasmic. MUT TP53 is modified in much the same manner but some modifications to MUT TP53 result in a GoF that enhances tumorigenesis.

Figure 2

Frequent mutations of modified residues in the TP53 DBD. A space-filling dimer of the TP53 DBD bound to a representation of a response element based on the X-ray structure of Emamzadah et al. (2011) (residues 94-291; PDB 3TS8). The two subunits are colored gray or purple. The six modified residues that are more commonly mutated are shown in color (red or green in the different subunits) and are identified in one subunit. The structure is rotated 180° to give front and back views.

Figure 3

Modified residues in the TET of TP53. A space filling model of the TET (subunits colored purple, blue, green and gray) based on the X-ray structure of Jeffery et al. (1995) is shown (residues 325-356, PDB 1C26); the five residues that can be posttranslationally modified are colored red on one subunit and are labeled. The structure is rotated 180° to give front and back views.

Figure 4

Model for the regulation of WT (A) and MUT (B) TP53 by PIN1. DNA damage and oncogenic signaling activate both WT TP53 (WTp53) and MUT TP53 (Mutp53) through several common kinases, e.g. JNK1/2, p38MAPK, PKCδ, that phosphorylate the same residues in each (Table 1, Supp. Fig. S1) creating binding sites for PIN1. Activation of WT TP53 by PIN1 contributes to the DNA damage response and to mechanisms that may suppress tumor development (see text). In contrast, binding of PIN1 to MUT TP53 leads to MUT TP53-mediated sequestration of TP63 and the interaction of MUT TP53 with transcription factors such as ETS-1, NF-Y, SP1 and VDR. These interactions alter the transcription profile of cells to induce metastasis and activities that contribute to tumor development. PIN1 often is overexpressed in tumors.

Figure 5

The functions and locations of TP53 are modulated by methylation of lysines at its C terminus and the interactions of these with methyl-binding proteins in basal conditions and after DNA damage. TP53 is mono- or dimethylated at four lysines under basal conditions (Lys370Me1, Lys373Me2, L:ys382Me1) or after DNA damage (Lys370Me2, Lys362Me1, Lys382Me2) by at least six lysine methyltransferases (see text). These lysines as well as others and nearby serines and threonines also are subject to PTMs including ubiquitylation, neddylation (not shown), sumoylation (not shown), and phosphorylation. The choreography of these events is not well known.