ArticleThe Journal of clinical investigation2017
Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
What it found
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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.
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Who cites it
33 citing papers in PubMed, 45 citations in OpenAlex.
- Oncogenic p53 induces mitotic errors in lung cancer cells by recopying DNA replication forks conferring targetable proliferation advantage.Cell death and differentiation · 2026Article
- Mutant p53 Directs PARP to Regulate Replication Stress and Drive Breast Cancer Metastasis.bioRxiv : the preprint server for biology · 2026Article
- Tumor-Tissue Boundaries as Instructive Interfaces in Breast Cancer Cell Invasion.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The Multifaceted Role of p53 in Cancer Molecular Biology: Insights for Precision Diagnosis and Therapeutic Breakthroughs.Biomolecules · 2025Review
- Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma.Cancer discovery · 2025Article
- The Role of p53 Mutations in Early and Late Response to Mitotic Aberrations.Biomolecules · 2025Review
- From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy.Biomarker research · 2024Review
- Targeting mutant p53: a key player in breast cancer pathogenesis and beyond.Cell communication and signaling : CCS · 2024Review
- Oncogenic Mutant p53 Sensitizes Non-Small Cell Lung Cancer Cells to Proteasome Inhibition via Oxidative Stress-Dependent Induction of Mitochondrial Apoptosis.Cancer research communications · 2024Article
- Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy.Cancer communications (London, England) · 2024Review
- Rewired mNature communications · 2023Article
- Gain-of-Function Variomics and Multi-omics Network Biology for Precision Medicine.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Reactivation of mutant p53 in esophageal squamous cell carcinoma by isothiocyanate inhibits tumor growth.Frontiers in pharmacology · 2023Article
- Mutant p53 in cancer: from molecular mechanism to therapeutic modulation.Cell death & disease · 2022Review
- Disrupted control of origin activation compromises genome integrity upon destabilization of Polε and dysfunction of the TRP53-CDKN1A/P21 axis.Cell reports · 2022Article
- Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients.Nature communications · 2022Article
- Article
- The oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of PLK3.Nature communications · 2021Article
- Oligomerization of Mutant p53 R273H is not Required for Gain-of-Function Chromatin Associated Activities.Frontiers in cell and developmental biology · 2021Article
- Chaperones and Ubiquitin Ligases Balance Mutant p53 Protein Stability in Esophageal and Other Digestive Cancers.Cellular and molecular gastroenterology and hepatology · 2021Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Gain-of-function (GOF) p53 mutations are observed frequently in most intractable human cancers and establish dependency for tumor maintenance and progression. While some of the genes induced by GOF p53 have been implicated in more rapid cell proliferation compared with p53-null cancer cells, the mechanism for dependency of tumor growth on mutant p53 is unknown. This report reveals a therapeutically targetable mechanism for GOF p53 dependency. We have shown that GOF p53 increases DNA replication origin firing, stabilizes replication forks, and promotes micronuclei formation, thus facilitating the proliferation of cells with genomic abnormalities. In contrast, absence or depletion of GOF p53 leads to decreased origin firing and a higher frequency of fork collapse in isogenic cells, explaining their poorer proliferation rate. Following genome-wide analyses utilizing ChIP-Seq and RNA-Seq, GOF p53-induced origin firing, micronuclei formation, and fork protection were traced to the ability of GOF p53 to transactivate cyclin A and CHK1. Highlighting the therapeutic potential of CHK1's role in GOF p53 dependency, experiments in cell culture and mouse xenografts demonstrated that inhibition of CHK1 selectively blocked proliferation of cells and tumors expressing GOF p53. Our data suggest the possibility that checkpoint inhibitors could efficiently and selectively target cancers expressing GOF p53 alleles.
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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.