ArticleThe Journal of clinical investigation2015
Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT.
Article in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed, 140 citations in OpenAlex.
- Sensitivity analysis of cell fate trajectories from single-cell transcriptomics.Bioinformatics (Oxford, England) · 2026Article
- CALR/HIF-1α Positive Feedback Loop Drives CALR Upregulation to Promote EMT-Mediated Bladder Cancer Progression via ROS/AKT Axis.Cancer science · 2026Article
- Integrated approaches to sensitizing melanoma to radiotherapy.Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] · 2026Review
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- PC3/Tis21/BTG2 and BTG1 genes: regulators of the cell cycle and neurogenesis, as well as tumor suppressors in malignant brain tumors.Frontiers in cell and developmental biology · 2026Review
- Diet-induced dyslipidemia enhances IFN-γ production in mycolic acid-specific T cells and affects mycobacterial control.Mucosal immunology · 2025Article
- Crosstalk between cancer‑associated fibroblasts and inflammation in tumor microenvironment: A novel perspective in cancer therapy (Review).Oncology reports · 2025Review
- UPR-induced intracellular C5aR1 promotes adaptation to the hypoxic tumour microenvironment.Cell death & disease · 2025Article
- Elucidating the multifaceted role and therapeutic potential of Sulf-2 in human tumor biology.Biomarkers in medicine · 2025Review
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- Cd248a regulates pericyte development and viability in zebrafish.Communications biology · 2025Article
- Structure and function of MDM2 and MDM4 in health and disease.The Biochemical journal · 2025Review
- Myeloid deficiency of heparan sulfate 6-O-endosulfatases impairs bone marrow hematopoiesis.Matrix biology : journal of the International Society for Matrix Biology · 2024Article
- Genome-Wide Analysis of p53 Targets Reveals SCN2A as a Novel Player in p53-Induced Cell Arrest in HPV-Positive Cells.Viruses · 2024Article
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- Dichotomous transactivation domains contribute to growth inhibitory and promotion functions of TAp73.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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- Differential effect of plakoglobin in restoring the tumor suppressor activities of p53-R273H vs. p53-R175H mutants.PloS one · 2024Article
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- RUNX1-Regulated Signaling Pathways in Ovarian Cancer.Biomedicines · 2023Review
26 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Restoration of hypoxia-induced apoptosis in tumors harboring p53 mutations has been proposed as a potential therapeutic strategy; however, the transcriptional targets that mediate hypoxia-induced p53-dependent apoptosis remain elusive. Here, we demonstrated that hypoxia-induced p53-dependent apoptosis is reliant on the DNA-binding and transactivation domains of p53 but not on the acetylation sites K120 and K164, which, in contrast, are essential for DNA damage-induced, p53-dependent apoptosis. Evaluation of hypoxia-induced transcripts in multiple cell lines identified a group of genes that are hypoxia-inducible proapoptotic targets of p53, including inositol polyphosphate-5-phosphatase (INPP5D), pleckstrin domain-containing A3 (PHLDA3), sulfatase 2 (SULF2), B cell translocation gene 2 (BTG2), cytoplasmic FMR1-interacting protein 2 (CYFIP2), and KN motif and ankyrin repeat domains 3 (KANK3). These targets were also regulated by p53 in human cancers, including breast, brain, colorectal, kidney, bladder, and melanoma cancers. Downregulation of these hypoxia-inducible targets associated with poor prognosis, suggesting that hypoxia-induced apoptosis contributes to p53-mediated tumor suppression and treatment response. Induction of p53 targets, PHLDA3, and a specific INPP5D transcript mediated apoptosis in response to hypoxia through AKT inhibition. Moreover, pharmacological inhibition of AKT led to apoptosis in the hypoxic regions of p53-deficient tumors and consequently increased radiosensitivity. Together, these results identify mediators of hypoxia-induced p53-dependent apoptosis and suggest AKT inhibition may improve radiotherapy response in p53-deficient tumors.
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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.