ArticleBMC cancer2011
A p53-independent role for the MDM2 antagonist Nutlin-3 in DNA damage response initiation.
Article in BMC cancer, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 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.
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Who cites it
44 citing papers in PubMed, 77 citations in OpenAlex.
- The MDM2-p53 Axis in Osteosarcoma: Current Understanding of Regulatory Mechanisms and Targeted Therapeutic Strategies.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Structure and function of MDM2 and MDM4 in health and disease.The Biochemical journal · 2025Review
- Targeting MDM2 affects spastin protein levels and functions: implications for HSP treatment.Cell death discovery · 2025Article
- Excessive MYC-topoisome activity triggers acute DNA damage, MYC degradation, and replacement by a p53-topoisome.Molecular cell · 2024Article
- Integrated stress response (ISR) activation and apoptosis through HRI kinase by PG3 and other p53 pathway-restoring cancer therapeutics.Oncotarget · 2024Article
- Coronin 2B deficiency induces nucleolar stress and neuronal apoptosis.Cell death & disease · 2024Article
- Understanding cellular senescence: pathways involved, therapeutics and longevity aiding.Cell cycle (Georgetown, Tex.) · 2023Review
- Article
- MDM2 inhibitors, nutlin-3a and navtemadelin, retain efficacy in human and mouse cancer cells cultured in hypoxia.Scientific reports · 2023Article
- Examining Stripes on a Herd of Zebras: Impact of Genomic Matching for Ultrarare Sarcomas in Phase 1 Clinical Trials (SAMBA 102).Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- The MDM2 Inhibitor Navtemadlin Arrests Mouse Melanoma GrowthCancer research communications · 2022Article
- Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?Cellular & molecular biology letters · 2021Review
- Methylglyoxal induces p53 activation and inhibits mTORC1 in human umbilical vein endothelial cells.Scientific reports · 2021Article
- Urolithin A induces prostate cancer cell death in p53-dependent and in p53-independent manner.European journal of nutrition · 2020Article
- Cisplatin in Combination with MDM2 Inhibition Downregulates Rad51 Recombinase in a Bimodal Manner to Inhibit Homologous Recombination and Augment Tumor Cell Kill.Molecular pharmacology · 2020Article
- Role of p53 in the Regulation of Cellular Senescence.Biomolecules · 2020Review
- RINT1 Loss Impairs Retinogenesis Through TRP53-Mediated Apoptosis.Frontiers in cell and developmental biology · 2020Article
- RITA requires eIF2α-dependent modulation of mRNA translation for its anti-cancer activity.Cell death & disease · 2019Article
- A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma.Journal of experimental & clinical cancer research : CR · 2018Article
- Role of Mdm2 and Mdmx in DNA repair.Journal of molecular cell biology · 2017Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
backgroundThe mammalian DNA-damage response (DDR) has evolved to protect genome stability and maximize cell survival following DNA-damage. One of the key regulators of the DDR is p53, itself tightly regulated by MDM2. Following double-strand DNA breaks (DSBs), mediators including ATM are recruited to the site of DNA-damage. Subsequent phosphorylation of p53 by ATM and ATM-induced CHK2 results in p53 stabilization, ultimately intensifying transcription of p53-responsive genes involved in DNA repair, cell-cycle checkpoint control and apoptosis.
methodsIn the current study, we investigated the stabilization and activation of p53 and associated DDR proteins in response to treatment of human colorectal cancer cells (HCT116p53+/+) with the MDM2 antagonist, Nutlin-3.
resultsUsing immunoblotting, Nutlin-3 was observed to stabilize p53, and activate p53 target proteins. Unexpectedly, Nutlin-3 also mediated phosphorylation of p53 at key DNA-damage-specific serine residues (Ser15, 20 and 37). Furthermore, Nutlin-3 induced activation of CHK2 and ATM - proteins required for DNA-damage-dependent phosphorylation and activation of p53, and the phosphorylation of BRCA1 and H2AX - proteins known to be activated specifically in response to DNA damage. Indeed, using immunofluorescent labeling, Nutlin-3 was seen to induce formation of γH2AX foci, an early hallmark of the DDR. Moreover, Nutlin-3 induced phosphorylation of key DDR proteins, initiated cell cycle arrest and led to formation of γH2AX foci in cells lacking p53, whilst γH2AX foci were also noted in MDM2-deficient cells.
conclusionTo our knowledge, this is the first solid evidence showing a secondary role for Nutlin-3 as a DDR triggering agent, independent of p53 status, and unrelated to its role as an MDM2 antagonist.
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