ArticleThe American journal of pathology2010
Iron-dependent regulation of MDM2 influences p53 activity and hepatic carcinogenesis.
Article in The American journal of pathology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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Who cites it
39 citing papers in PubMed, 1 synthesis or guideline pooled it, 74 citations in OpenAlex.
- The Role of Iron Chelation Therapy in Colorectal Cancer: A Systematic Review on Its Mechanisms and Therapeutic Potential.Cancer medicine · 2025Pooled it
- MDM2 Alters Cellular Iron Homeostasis by Promoting the Degradation of Proteins Involved in Iron Storage and Iron Export.Current issues in molecular biology · 2026Article
- The solute carrier family 11 transporters: a bridge between iron homeostasis and tumor biology.Cell communication and signaling : CCS · 2025Review
- Tumour stemness and poor clinical outcomes in haemochromatosis patients with hepatocellular carcinoma.Journal of clinical pathology · 2024Article
- Hormone replacement therapy for postmenopausal atherosclerosis is offset by late age iron deposition.eLife · 2023Article
- Oxidative Stress-Induced Cellular Senescence: Is Labile Iron the Connecting Link?Antioxidants (Basel, Switzerland) · 2023Review
- Role of p53 suppression in the pathogenesis of hepatocellular carcinoma.World journal of gastrointestinal pathophysiology · 2023Review
- Review
- Upregulated microRNA-450b-5p represses the development of acute liver failure via modulation of liver function, inflammatory response, and hepatocyte apoptosis.Immunity, inflammation and disease · 2023Article
- FTH1 indicates poor prognosis and promotes metastasis in head and neck squamous cell carcinoma.PeerJ · 2023Article
- Reversing oncogenic transformation with iron chelation.Oncotarget · 2021Review
- Review
- Emerging Roles of the Tumor Suppressor p53 in Metabolism.Frontiers in cell and developmental biology · 2021Review
- The role of zinc transporter proteins as predictive and prognostic biomarkers of hepatocellular cancer.PeerJ · 2021Article
- Molecular Targets of Ferroptosis in Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2021Review
- Iron and Cancer: 2020 Vision.Cancer research · 2020Review
- Deferasirox-Dependent Iron Chelation Enhances Mitochondrial Dysfunction and Restores p53 Signaling by Stabilization of p53 Family Members in Leukemic Cells.International journal of molecular sciences · 2020Article
- Iron: The cancer connection.Molecular aspects of medicine · 2020Review
- Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer.Molecular metabolism · 2020Review
- Mdm2 is a target and mediator of IRP2 in cell growth control.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Iron overload is a risk factor for hepatocarcinoma, but the pathways involved are poorly characterized. Gene expression analysis in immortalized mouse hepatocytes exposed to iron or the iron chelator deferoxamine revealed that iron downregulated, whereas deferoxamine upregulated, mRNA levels of mouse double minute gene 2 (MDM2), the ubiquitin ligase involved in the degradation of the oncosuppressor p53. Regulation of MDM2 by iron status was observed at protein levels in mouse hepatocytes and rat liver, and was associated with specular changes in p53 expression. Iron dependent regulation of MDM2/p53 was confirmed ex-vivo in human monocytes, by manipulation of iron pool and in a genetic model of iron deficiency, leading to modulation of p53 target genes involved in the antioxidant response and apoptosis. Iron status influenced p53 ubiquitination and degradation rate, and the MDM2 inhibitor nutlin increased p53 levels in iron-depleted cells. Furthermore, nutlin enhanced the antiproliferative activity of deferoxamine in HepG2 hepatoblastoma cells. The MDM2 -309T > G promoter polymorphism, determining increased MDM2 and lower p53 activity, was associated with higher risk of hepatocarcinoma in cirrhotic patients with hemochromatosis, and with HFE mutations in patients with hepatocarcinoma without hemochromatosis, suggesting an interaction between MDM2 and iron in the pathogenesis of hepatocarcinoma. In conclusion, iron status influences p53 activity and antioxidant response by modulating MDM2 expression. MDM2 inhibitors may enhance the antiproliferative activity of iron chelators.
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