ArticleNature communications2022
PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 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
20 citing papers in PubMed, 29 citations in OpenAlex.
- Transient p53/p21 activation selectively protects healthy human hair follicles and their stem cells from chemotherapy.The Journal of clinical investigation · 2026Article
- Regulation of G protein-coupled receptor kinase 2 and its role in tumors.Journal of translational medicine · 2026Review
- Targeting the p53 pathway to treat atypical teratoid rhabdoid tumors.Neuro-oncology pediatrics · 2026Article
- Gain-of-function PPM1D mutations attenuate ischemic stroke.Cell death and differentiation · 2025Article
- Safety profile of sikamat virus and its oncolytic potential in leukemic cells and cancer stem cells.Scientific reports · 2025Article
- Non-Canonical STING-PERK Pathway Modulation of Cellular Senescence and Therapeutic Response in Sepsis-Associated Acute Kidney Injury.Inflammation · 2025Article
- Article
- Harnessing p53 for targeted cancer therapy: new advances and future directions.Transcription · 2025Review
- Case report of two patients with refractory HIV-related B-cell lymphoma treated with the monoclonal antibody glofitamab for secondary central nervous system involvement.Frontiers in oncology · 2025Article
- Determinants of p53 DNA binding, gene regulation, and cell fate decisions.Cell death and differentiation · 2024Review
- ATF4 in cellular stress, ferroptosis, and cancer.Archives of toxicology · 2024Review
- Review
- Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy.Cancer communications (London, England) · 2024Review
- Article
- Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes.Nature cardiovascular research · 2023Article
- Shared gene targets of the ATF4 and p53 transcriptional networks.bioRxiv : the preprint server for biology · 2023Article
- Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies.MedComm · 2023Review
- EBNA2 mediates lipid metabolism and tumorigenesis through activation of ATF4 pathway.American journal of cancer research · 2023Article
- Shared Gene Targets of the ATF4 and p53 Transcriptional Networks.Molecular and cellular biology · 2023Article
- A Retrospective Study of the Correlation Between Next-Generation Sequencing and Immunohistochemical Detection of TP53 in Colorectal Cancer.Technology in cancer research & treatmentArticle
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The p53 transcription factor is a master regulator of cellular stress responses inhibited by repressors such as MDM2 and the phosphatase PPM1D. Activation of p53 with pharmacological inhibitors of its repressors is being tested in clinical trials for cancer therapy, but efficacy has been limited by poor induction of tumor cell death. We demonstrate that dual inhibition of MDM2 and PPM1D induces apoptosis in multiple cancer cell types via amplification of the p53 transcriptional program through the eIF2α-ATF4 pathway. PPM1D inhibition induces phosphorylation of eIF2α, ATF4 accumulation, and ATF4-dependent enhancement of p53-dependent transactivation upon MDM2 inhibition. Dual inhibition of p53 repressors depletes heme and induces HRI-dependent eIF2α phosphorylation. Pharmacological induction of eIF2α phosphorylation synergizes with MDM2 inhibition to induce cell death and halt tumor growth in mice. These results demonstrate that PPM1D inhibits both the p53 network and the integrated stress response controlled by eIF2α-ATF4, with clear therapeutic implications.
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What Socratic 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 Socratic graph.