ArticleHaematologica2009
Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes.
Article in Haematologica, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 120 citations in OpenAlex.
- TFR2 p.A75V mutation aggravates liver iron overload in alcoholic liver disease via ERK pathway.Journal of molecular medicine (Berlin, Germany) · 2026Article
- Hepatocyte Toll-like receptors contribute to the hepcidin inflammatory response to pathogens and pathogen-derived ligands.HemaSphere · 2025Article
- RAS signaling pathway is essential in regulating PIEZO1-mediated hepatic iron overload in dehydrated hereditary stomatocytosis.American journal of hematology · 2025Article
- Serum Iron Overload Activates the SMAD Pathway and Hepcidin Expression of Hepatocytes via SMURF1.Journal of clinical and translational hepatology · 2024Article
- Activation of STAT and SMAD Signaling Induces Hepcidin Re-Expression as a Therapeutic Target for β-Thalassemia Patients.Biomedicines · 2022Review
- Coordination of iron homeostasis by bone morphogenetic proteins: Current understanding and unanswered questions.Developmental dynamics : an official publication of the American Association of Anatomists · 2022Article
- Effects of Exogenous Transferrin on the Regulation of Iron Metabolism and Erythropoiesis in Iron Deficiency With or Without Anemia.Frontiers in physiology · 2022Article
- Iron Accumulation and Lipid Peroxidation in the Aging Retina: Implication of Ferroptosis in Age-Related Macular Degeneration.Aging and disease · 2021Review
- Transferrin Receptors in Erythropoiesis.International journal of molecular sciences · 2020Review
- Auranofin mitigates systemic iron overload and induces ferroptosis via distinct mechanisms.Signal transduction and targeted therapy · 2020Article
- Deregulation of Hepatic Mek1/2⁻Erk1/2 Signaling Module in Iron Overload Conditions.Pharmaceuticals (Basel, Switzerland) · 2019Article
- Iron Regulation: Macrophages in Control.Pharmaceuticals (Basel, Switzerland) · 2018Review
- Iron as a Therapeutic Target inPharmaceuticals (Basel, Switzerland) · 2018Review
- Haemochromatosis.Nature reviews. Disease primers · 2018Review
- DNA methylation of hepatic iron sensing genes and the regulation of hepcidin expression.PloS one · 2018Article
- Modelling Systemic Iron Regulation during Dietary Iron Overload and Acute Inflammation: Role of Hepcidin-Independent Mechanisms.PLoS computational biology · 2017Article
- Increased hepcidin in transferrin-treated thalassemic mice correlates with increased liver BMP2 expression and decreased hepatocyte ERK activation.Haematologica · 2016Article
- Effects of developmental iron deficiency and post-weaning iron repletion on the levels of iron transporter proteins in rats.Nutrition research and practice · 2015Article
- HJV and HFE Play Distinct Roles in Regulating Hepcidin.Antioxidants & redox signaling · 2015Article
- Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidin.Journal of molecular medicine (Berlin, Germany) · 2015Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe circulating hormone hepcidin plays a central role in iron homeostasis. Our goal was to establish an ex vivo iron-sensing model and to characterize the molecular mechanisms linking iron to hepcidin. DESIGN AND
methodsMurine hepatocytes were isolated by the collagenase method, either from wild type or HFE knockout mice, and cultured 42 h without serum before treatments.
resultsAfter 42 h of serum-free culture, hepcidin gene expression was undetectable in the hepatocytes. Hepcidin gene expression could, however, be re-activated by an additional 24 h of incubation with 10% serum. Interestingly, addition of 30 microM holotransferrin consistently increased serum-dependent hepcidin levels 3- to 5-fold. The effects of serum and serum+holotransferrin were direct, transcriptional, independent of de novo protein synthesis and required the presence of bone morphogenetic protein. Transferrin receptor-2 activation by its ligand holotransferrin led to extracellular signal regulated kinase (ERK)/mitogen activated protein kinase pathway stimulation and the ERK specific inhibitor U0-126 blunted holotransferrin-mediated induction of hepcidin. ERK activation by holotransferrin provoked increased levels of phospho-Smad1/5/8 highlighting cross-talk between the bone morphogenetic protein/hemojuvelin and ERK1/2 pathways. Finally, we demonstrated, using hepatocytes isolated from Hfe(-/-) mice, that HFE was not critical for the hepcidin response to holotransferrin but important for basal hepcidin expression.
conclusionsWe demonstrate that hepatocytes are liver iron-sensor cells and that transferrin receptor-2, by signaling through the ERK1/2 pathway, and bone morphogenetic protein/hemojuvelin, by signaling through the Smad pathways, coordinately regulate the iron-sensing machinery linking holotransferrin to hepcidin.
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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.