Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

Abstract

Prion diseases are disorders that share several characteristics that are typical of many neurodegenerative diseases. Recently, several studies have extended the prion concept to pathological aggregation in malignant tumors involving misfolded p53, a tumor-suppressor protein. The aggregation of p53 and its coaggregation with p53 family members, p63 and p73, have been shown. Certain p53 mutants exert a dominant-negative regulatory effect on wild-type (WT) p53. The basis for this dominant-negative effect is that amyloid-like mutant p53 converts WT p53 into an aggregated species, leading to a gain-of-function (GoF) phenotype and the loss of its tumor-suppressor function. Recently, it was shown that p53 aggregates can be internalized by cells and can coaggregate with endogenous p53, corroborating the prion-like properties of p53 aggregates. The prion-like behavior of oncogenic p53 mutants provides an explanation for its dominant-negative and GoF properties, including the high metastatic potential of cancer cells carrying p53 mutations. The inhibition of p53 aggregation appears to represent a promising target for therapeutic intervention in patients with malignant tumors.

Figure 1.

The three-dimensional structure of p53. Active p53 is a tetrameric protein consisting of an oligomerization domain (OD), a DNA-binding domain (DBD), and a transactivation domain (TAD). Schematic representation (left) and crystal structures (right; PDB IDs: OD, 2J0Z; DBD, 2XWR; and TAD, 2L14) of p53 monomers (green, red, blue, and gold) in the predicted active conformation based on electron microscopy and small-angle X-ray-scattering reconstructions (Tidow et al. 2007; Melero et al. 2011).

Figure 2.

Effects of p53 mutation on its activity. Certain p53 mutants (1) lose wild-type (WT) activity (loss-of-function [LoF]); (2) acquire oncogenic activity without disturbing the activity of WT p53 (gain-of-function [GoF]); (3) inhibit the WT p53 protein via a dominant-negative effect and display oncogenic activity (GoF); and (4) inhibit the WT p53 protein via a dominant-negative effect but display no other activity (LoF). Dominant-negative mechanisms are exemplified (i.e., heterotetramers, aggregation, or coaggregation). Cellular partners (e.g., WT p53, p63, p73, HSPs, and proteins that have yet to be discovered [?]) coaggregate with mutant p53.

Figure 3.

Amyloid formation by the p53 DNA-binding domain (DBD). (A) Model of the p53 252-256 amyloid fibril generated based on molecular dynamics (MDs) simulations of the aggregation-prone sequence. (B) The DBD structure of p53 (PDB ID: 2XWR) (Natan et al. 2011) showing the amyloidogenic 251-258 region (red), Trp91/Arg174 (atomic detail), and equivalent sequence comparison.

Figure 4.

Domain structure and sequence comparisons of p53 family proteins. (A) The predominant domain structures of p53, p63, and p73, depicting the transactivation domain (TAD), DNA-binding domain (DBD), oligomerization domain (OD), and sterile α-motif (SAM) domains. (B) Sequence similarity scores for the comparison between p53, p63, and p73 (top), and between p63 and p73 (bottom). The similarity scores were generated based on the Clustal Omega (Sievers et al. 2011) gapped alignment of the full-length protein sequences using a 10-residue moving window average and considering the fully conserved, highly conserved, moderately conserved, nonconserved, and gapped positions.