Tumorigenic p53 mutants undergo common structural disruptions including conversion to α‐sheet structure

Abstract

The p53 protein is a commonly studied cancer target because of its role in tumor suppression. Unfortunately, it is susceptible to mutation‐associated loss of function; approximately 50% of cancers are associated with mutations to p53, the majority of which are located in the central DNA‐binding domain. Here, we report molecular dynamics simulations of wild‐type (WT) p53 and 20 different mutants, including a stabilized pseudo‐WT mutant. Our findings indicate that p53 mutants tend to exacerbate latent structural‐disruption tendencies, or vulnerabilities, already present in the WT protein, suggesting that it may be possible to develop cancer therapies by targeting a relatively small set of structural‐disruption motifs rather than a multitude of effects specific to each mutant. In addition, α‐sheet secondary structure formed in almost all of the proteins. α‐Sheet has been hypothesized and recently demonstrated to play a role in amyloidogenesis, and its presence in the reported p53 simulations coincides with the recent re‐consideration of cancer as an amyloid disease.

Targeting mutant p53 for cancer therapy: direct and indirect strategies

“…The development of p53-targeted drugs is particularly difficult because the agent must specifically target mutp53 in cancer cells while having no effect on normal cells harboring wtp53 [ 24 ]. Additionally, multiple p53 mutations result in various mutp53 protein structures that are difficult to target [ 25 ]. Major therapeutic strategies targeting p53 can be classified into two categories based on their p53 status: restoring wtp53 functions and eradicating mutp53 [ 8 , 26 – 28 ].…”

Transgenic construction and functional miRNA analysis identify the role of miR-7 in prostate cancer suppression

“…Evidence suggests that TP53 mutations play an important role in PCa chemotherapy resistance, thus preventing several patients with advanced PCa from benefiting from this first-line treatment [9,10]. However, directly targeting TP53 mutations in tumor treatment due to the functional and structural complexity of p53 wild-type proteins under physiological conditions, remains largely unsuccessful [11,12]. Therefore, there is an urgent need for a deeper understanding of the role of p53 in tumorigenesis and examining alternative anti-tumor strategies for patients carrying TP53 mutations.…”