Mutant p53: one name, many proteins

Abstract

There is now strong evidence that mutation not only abrogates p53 tumor-suppressive functions, but in some instances can also endow mutant proteins with novel activities. Such neomorphic p53 proteins are capable of dramatically altering tumor cell behavior, primarily through their interactions with other cellular proteins and regulation of cancer cell transcriptional programs. Different missense mutations in p53 may confer unique activities and thereby offer insight into the mutagenic events that drive tumor progression. Here we review mechanisms by which mutant p53 exerts its cellular effects, with a particular focus on the burgeoning mutant p53 transcriptome, and discuss the biological and clinical consequences of mutant p53 gain of function.

Figures

Figure 1.

TP53 mutational spectrum in human cancers. (A) TP53 missense mutation data for human cancer patients (N = 19,262) were obtained from the p53 International Agency for Research on Cancer (IARC) database and plotted as a function of amino acid position. Schematic of the p53 protein with domain structures illustrated. (TAD) Transactivation domain (1–42); (PRD) proline-rich domain (40–92), which also contains a second transactivation domain; (DBD) DNA-binding domain (101–306); (OD) oligomerization domain (307–355), also contains a nuclear export signal; (CTD) C-terminal regulatory domain (356–393), also contains three nuclear localization signals (data adapted from http://p53.free.fr). (B) Table for the six “hot spot” residues in p53 with corresponding frequency of any mutation at a given residue. TP53 mutation data for human cancer patients (N = 25,902) were obtained from the p53 database (http://p53.free.fr). (C) Table for the most common missense mutations at “hot spot” residues in p53 with corresponding frequency of particular mutation. TP53 mutation data for human cancer patients (N = 25,902) were obtained from the p53 database (http://p53.free.fr).

Figure 2.

Mechanisms of mutant p53 gain of function. There are multiple proposed mechanisms that account for different mutant p53 gain-of-function activities. These include both transcriptional and nontranscriptional mechanisms: (A) Physical interaction with p53 family members p63 and p73 to inhibit transactivation of their respective target genes. (B) Interaction with and recruitment by cellular transcription factors to their cognate binding sites, leading to more robust transactivation of their respective target genes. Examples of this mechanism include NF-Y, SREBP-2, Sp1, Ets-1, and VDR. (C) Structure-specific DNA binding by mutant p53, resulting in transcriptional regulation of the relevant promoter. The most well-described example is the interaction of mutant p53 and matrix attachment regions (MARs). (D) “Direct” recruitment of mutant p53 to unique sequence-specific DNA elements and/or unique chromatin landscapes. The dashed gray arrow indicates that there is currently little evidence to support this proposed mechanism. (E) Physical interaction with other cellular proteins that are not transcription factors, such as TopB1, Pin1, MRE11, PML, and others.