ArticleProceedings of the National Academy of Sciences of the United States of America2017
Multisite aggregation of p53 and implications for drug rescue.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
50 citing papers in PubMed, 1 synthesis or guideline pooled it, 85 citations in OpenAlex.
- Targeting p53 pathways: mechanisms, structures, and advances in therapy.Signal transduction and targeted therapy · 2023Pooled it
- Multi-Site Aggregation of p53: Insights from Self- and Co-Aggregation of Multiple Aggregation-Prone Regions.ACS omega · 2026Article
- Cancer-linked aggregation of p53 is driven by sequence-encoded frustration, solvation, and hydrophobic gating absent in its paralogs.Communications chemistry · 2026Article
- p53: from understanding its structure to advances in therapeutic targeting.Signal transduction and targeted therapy · 2026Review
- Trifluridine/tipiracil induces ferroptosis by targeting p53 via the p53-SLC7A11 axis in colorectal cancer 3D organoids.Cell death & disease · 2025Article
- Mesoscopic p53-rich clusters represent a new class of protein condensates.Biophysics reviews · 2025Review
- Vaccines targeting p53 mutants elicit anti-tumor immunity.Cancer letters · 2025Article
- Covalent Fragments Acting as Tyrosine Mimics for Mutant p53-Y220C Rescue by Nucleophilic Aromatic Substitution.ACS pharmacology & translational science · 2024Article
- Multiscale simulations reveal the driving forces of p53C phase separation accelerated by oncogenic mutations.Chemical science · 2024Article
- Anticancer therapeutic strategies for targeting mutant p53-Y220C.Journal of biomedical research · 2024Article
- Review
- Physiology and pharmacological targeting of phase separation.Journal of biomedical science · 2024Review
- Phage libraries screening on P53: Yield improvement by zinc and a new parasites-integrating analysis.PloS one · 2024Article
- Structure-Reactivity Studies of 2-Sulfonylpyrimidines Allow Selective Protein Arylation.Bioconjugate chemistry · 2023Article
- Article
- PRIMA-1 inhibits Y220C p53 amyloid aggregation and synergizes with cisplatin in hepatocellular carcinoma.Frontiers in molecular biosciences · 2023Article
- Targeting mutant p53 stabilization for cancer therapy.Frontiers in pharmacology · 2023Review
- Therapeutic Strategies to Activate p53.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Characterization of full-length p53 aggregates and their kinetics of formation.Biophysical journal · 2022Article
- Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C.ACS pharmacology & translational science · 2022Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Protein aggregation is involved in many diseases. Often, a unique aggregation-prone sequence polymerizes to form regular fibrils. Many oncogenic mutants of the tumor suppressor p53 rapidly aggregate but form amorphous fibrils. A peptide surrounding Ile254 is proposed to be the aggregation-driving sequence in cells. We identified several different aggregating sites from limited proteolysis of harvested aggregates and effects of mutations on kinetics and products of aggregation. We present a model whereby the amorphous nature of the aggregates results from multisite branching of polymerization after slow unfolding of the protein, which may be a common feature of aggregation of large proteins. Greatly lowering the aggregation propensity of any one single site, including the site of Ile254, by mutation did not inhibit aggregation in vitro because aggregation could still occur via the other sites. Inhibition of an individual site is, accordingly, potentially unable to prevent aggregation in vivo. However, cancer cells are specifically killed by peptides designed to inhibit the Ile254 sequence and further aggregation-driving sequences that we have found. Consistent with our proposed mechanism of aggregation, we found that such peptides did not inhibit aggregation of mutant p53 in vitro. The cytotoxicity was not eliminated by knockdown of p53 in 2D cancer cell cultures. The peptides caused rapid cell death, much faster than usually expected for p53-mediated transcription-dependent apoptosis. There may also be non-p53 targets for those peptides in cancer cells, such as p63, or the peptides may alter other interactions of partly denatured p53 with receptors.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.