Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver
Open accessAbstract
Although hepcidin expression was shown to be induced by the BMP/Smad signaling pathway, it is not yet known how iron regulates this pathway and what its exact molecular targets are. We therefore assessed genome-wide liver transcription profiles of mice of 2 genetic backgrounds fed iron-deficient, -balanced, or -enriched diets. Among 1419 transcripts significantly modulated by the dietary iron content, 4 were regulated similarly to the hepcidin genes Hamp1 and Hamp2. They are coding for Bmp6, Smad7, Id1, and Atoh8 all related to the Bmp/Smad pathway. As shown by Western blot analysis, variations in Bmp6 expression induced by the diet iron content have for functional consequence similar changes in Smad1/5/8 phosphorylation that leads to formation of heteromeric complexes with Smad4 and their translocation to the nucleus. Gene expression variations induced by secondary iron deficiency or iron overload were compared with those consecutive to Smad4 and Hamp1 deficiency. Iron overload developed by Smad4- and Hamp1-deficient mice also increased Bmp6 transcription. However, as shown by analysis of mice with liver-specific disruption of Smad4, activation of Smad7, Id1, and Atoh8 transcription by iron requires Smad4. This study points out molecules that appear to play a critical role in the control of systemic iron balance.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
BMP6 expression is regulated by iron, possibly in the context of an antioxidant response, controlled by NRF2.
“BMP6 expression is regulated by iron,42 possibly in the context of an antioxidant response, controlled by NRF2.43”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [42]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
DAVID: Database for Annotation, Visualization, and Integrated Discovery
Dennis, G., Sherman, B. T., Hosack, D. A., Yang, J., Gao, W., Lane, H. C., & Lempicki, R. A. (2003) · Genome Biology · doi:10.1186/gb-2003-4-5-p3 · Cited by 9,327 · see citing works
Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization
Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., Ganz, T., & Kaplan, J. (2004) · Science · doi:10.1126/science.1104742 · Cited by 4,803 · see citing works
Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K., & Ganz, T. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200420945 · Cited by 2,650 · see citing works
The RIN: an RNA integrity number for assigning integrity values to RNA measurements
Schroeder, A., Mueller, O., Stocker, S., Salowsky, R., Leiber, M., Gassmann, M., Lightfoot, S., Menzel, W., Granzow, M., & Ragg, T. (2006) · BMC Molecular Biology · doi:10.1186/1471-2199-7-3 · Cited by 2,623 · see citing works
Pigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P., & Loréal, O. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008923200 · Cited by 1,697 · see citing works
Nicolas, G., Chauvet, C., Viatte, L., Danan, J. L., Bigard, X., Devaux, I., Beaumont, C., Kahn, A., & Vaulont, S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215686 · Cited by 1,214 · see citing works
Self-citationBone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression
Babitt, J. L., Huang, F. W., Wrighting, D. M., Xia, Y., Sidis, Y., Samad, T. A., Campagna, J. A., Chung, R. T., Schneyer, A. L., Woolf, C. J., et al. (2006) · Nature Genetics · doi:10.1038/ng1777 · Cited by 1,026 · see citing works
Mutations in HFE2 cause iron overload in chromosome 1q–linked juvenile hemochromatosis
Papanikolaou, G., Samuels, M. E., Ludwig, E. H., MacDonald, M. L. E., Franchini, P. L., Dubé, M.-P., Andres, L., MacFarlane, J., Sakellaropoulos, N., Politou, M., et al. (2004) · Nature Genetics · doi:10.1038/ng1274 · Cited by 974 · see citing works
The Transferrin Receptor Modulates Hfe-Dependent Regulation of Hepcidin Expression
Schmidt, P. J., Toran, P. T., Giannetti, A. M., Bjorkman, P. J., & Andrews, N. C. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.11.016 · Cited by 345 · see citing works
Truksa, J., Peng, H., Lee, P., & Beutler, E. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603124103 · Cited by 309 · see citing works
Lin, L., Valore, E. V., Nemeth, E., Goodnough, J. B., Gabayan, V., & Ganz, T. (2007) · Blood · doi:10.1182/blood-2007-04-087593 · Cited by 267 · see citing works
Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis
Lesbordes-Brion, J.-C., Viatte, L., Bennoun, M., Lou, D.-Q., Ramey, G., Houbron, C., Hamard, G., Kahn, A., & Vaulont, S. (2006) · Blood · doi:10.1182/blood-2006-02-003376 · Cited by 257 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Ganz, T., & Nemeth, E. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.01.014 · Cited by 1,282 · see citing works
Ganz, T. (2013) · Physiological Reviews · doi:10.1152/physrev.00008.2013 · Cited by 1,122 · see citing works
Identification of erythroferrone as an erythroid regulator of iron metabolism
Kautz, L., Jung, G., Valore, E. V., Rivella, S., Nemeth, E., & Ganz, T. (2014) · Nature Genetics · doi:10.1038/ng.2996 · Cited by 1,127 · see citing works
Self-citationRegulation of cellular iron metabolism
Wang, J., & Pantopoulos, K. (2011) · Biochemical Journal · doi:10.1042/bj20101825 · Cited by 986 · see citing works
Hepcidin and iron regulation, 10 years later
Ganz, T. (2011) · Blood · doi:10.1182/blood-2011-01-258467 · Cited by 962 · see citing works
BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism
Andriopoulos Jr, B., Corradini, E., Xia, Y., Faasse, S. A., Chen, S., Grgurevic, L., Knutson, M. D., Pietrangelo, A., Vukicevic, S., Lin, H. Y., et al. (2009) · Nature Genetics · doi:10.1038/ng.335 · Cited by 769 · see citing works
Iron metabolism and iron disorders revisited in the hepcidin era
Camaschella, C., Nai, A., & Silvestri, L. (2020) · Haematologica · doi:10.3324/haematol.2019.232124 · Cited by 734 · see citing works
“BMP6 expression is regulated by iron, 42 possibly in the context of an antioxidant response, controlled by NRF2.”
Camaschella, C. (2019) · Blood · doi:10.1182/blood-2018-05-815944 · Cited by 702 · see citing works
Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment
Pietrangelo, A. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.06.013 · Cited by 615 · see citing works
Lack of the bone morphogenetic protein BMP6 induces massive iron overload
Meynard, D., Kautz, L., Darnaud, V., Canonne-Hergaux, F., Coppin, H., & Roth, M.-P. (2009) · Nature Genetics · doi:10.1038/ng.320 · Cited by 587 · see citing works
Self-citationRegulation of iron transport and the role of transferrin
Gkouvatsos, K., Papanikolaou, G., & Pantopoulos, K. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.10.013 · Cited by 518 · see citing works
Liver iron sensing and body iron homeostasis
Wang, C.-Y., & Babitt, J. L. (2019) · Blood · doi:10.1182/blood-2018-06-815894 · Cited by 360 · see citing works
Tanno, T., Porayette, P., Sripichai, O., Noh, S.-J., Byrnes, C., Bhupatiraju, A., Lee, Y. T., Goodnough, J. B., Harandi, O., Ganz, T., et al. (2009) · Blood · doi:10.1182/blood-2008-12-195503 · Cited by 352 · see citing works
An overview of molecular basis of iron metabolism regulation and the associated pathologies
Silva, B., & Faustino, P. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.03.011 · Cited by 300 · see citing works
Hepcidin regulation by innate immune and infectious stimuli
Armitage, A. E., Eddowes, L. A., Gileadi, U., Cole, S., Spottiswoode, N., Selvakumar, T. A., Ho, L.-P., Townsend, A. R. M., & Drakesmith, H. (2011) · Blood · doi:10.1182/blood-2011-04-351957 · Cited by 294 · see citing works
Hepcidin: regulation of the master iron regulator
Rishi, G., Wallace, D. F., & Subramaniam, V. N. (2015) · Bioscience Reports · doi:10.1042/bsr20150014 · Cited by 223 · see citing works
Corradini, E., Meynard, D., Wu, Q., Chen, S., Ventura, P., Pietrangelo, A., & Babitt, J. L. (2011) · Hepatology · doi:10.1002/hep.24359 · Cited by 194 · see citing works
Self-citationGuo, W., Bachman, E., Li, M., Roy, C. N., Blusztajn, J., Wong, S., Chan, S. Y., Serra, C., Jasuja, R., Travison, T. G., et al. (2013) · Aging Cell · doi:10.1111/acel.12052 · Cited by 192 · see citing works
Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats
Theurl, I., Schroll, A., Sonnweber, T., Nairz, M., Theurl, M., Willenbacher, W., Eller, K., Wolf, D., Seifert, M., Sun, C. C., et al. (2011) · Blood · doi:10.1182/blood-2011-03-345066 · Cited by 189 · see citing works
Besson-Fournier, C., Latour, C., Kautz, L., Bertrand, J., Ganz, T., Roth, M.-P., & Coppin, H. (2012) · Blood · doi:10.1182/blood-2012-02-411470 · Cited by 179 · see citing works
Self-citationIneffective erythropoiesis and regulation of iron status in iron loading anaemias
Camaschella, C., & Nai, A. (2016) · British Journal of Haematology · doi:10.1111/bjh.13820 · Cited by 172 · see citing works
Identification and Application of Gene Expression Signatures Associated with Lifespan Extension
Tyshkovskiy, A., Bozaykut, P., Borodinova, A. A., Gerashchenko, M. V., Ables, G. P., Garratt, M., Khaitovich, P., Clish, C. B., Miller, R. A., & Gladyshev, V. N. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.06.018 · Cited by 167 · see citing works
Review article: the iron overload syndromes
Siddique, A., & Kowdley, K. V. (2012) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2012.05051.x · Cited by 162 · see citing works
Casanovas, G., Mleczko-Sanecka, K., Altamura, S., Hentze, M. W., & Muckenthaler, M. U. (2009) · Journal of Molecular Medicine · doi:10.1007/s00109-009-0447-2 · Cited by 161 · see citing works
Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia
Nai, A., Pagani, A., Mandelli, G., Lidonnici, M. R., Silvestri, L., Ferrari, G., & Camaschella, C. (2012) · Blood · doi:10.1182/blood-2012-01-401885 · Cited by 161 · see citing works
Low hepcidin accounts for the proinflammatory status associated with iron deficiency
Pagani, A., Nai, A., Corna, G., Bosurgi, L., Rovere-Querini, P., Camaschella, C., & Silvestri, L. (2011) · Blood · doi:10.1182/blood-2011-02-337212 · Cited by 138 · see citing works
Genetics, genetic testing, and management of hemochromatosis: 15 years since hepcidin
Pietrangelo, A. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.06.045 · Cited by 136 · see citing works
Latour, C., Kautz, L., Besson-Fournier, C., Island, M.-L., Canonne-Hergaux, F., Loréal, O., Ganz, T., Coppin, H., & Roth, M.-P. (2014) · Hepatology · doi:10.1002/hep.26648 · Cited by 120 · see citing works
Self-citationCanali, S., Core, A. B., Zumbrennen-Bullough, K. B., Merkulova, M., Wang, C.-Y., Schneyer, A. L., Pietrangelo, A., & Babitt, J. L. (2016) · Endocrinology · doi:10.1210/en.2015-1747 · Cited by 113 · see citing works
Corradini, E., Schmidt, P. J., Meynard, D., Garuti, C., Montosi, G., Chen, S., Vukicevic, S., Pietrangelo, A., Lin, H. Y., & Babitt, J. L. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.07.044 · Cited by 109 · see citing works
Self-citationRole of Hepcidin in the Setting of Hypoferremia during Acute Inflammation
Deschemin, J.-C., & Vaulont, S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061050 · Cited by 89 · see citing works
Self-citationTmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice
Finberg, K. E., Whittlesey, R. L., & Andrews, N. C. (2011) · Blood · doi:10.1182/blood-2010-10-315507 · Cited by 81 · see citing works
Genetic mechanisms and modifying factors in hereditary hemochromatosis
Weiss, G. (2010) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2009.201 · Cited by 82 · see citing works
Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice
Bartnikas, T. B., Andrews, N. C., & Fleming, M. D. (2011) · Blood · doi:10.1182/blood-2010-05-287359 · Cited by 77 · see citing works
Enns, C. A., Ahmed, R., Wang, J., Ueno, A., Worthen, C., Tsukamoto, H., & Zhang, A.-S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060534 · Cited by 69 · see citing works
Frazer, D. M., Wilkins, S. J., Darshan, D., Badrick, A. C., McLaren, G. D., & Anderson, G. J. (2012) · British Journal of Haematology · doi:10.1111/j.1365-2141.2012.09104.x · Cited by 43 · see citing works
Tao, Y., Wu, Q., Guo, X., Zhang, Z., Shen, Y., & Wang, F. (2014) · British Journal of Haematology · doi:10.1111/bjh.12863 · Cited by 31 · see citing works
Induced Disruption of the Iron-Regulatory Hormone Hepcidin Inhibits Acute Inflammatory Hypoferraemia
Armitage, A. E., Lim, P. J., Frost, J. N., Pasricha, S.-R., Soilleux, E. J., Evans, E., Morovat, A., Santos, A., Diaz, R., Biggs, D., et al. (2016) · Journal of Innate Immunity · doi:10.1159/000447713 · Cited by 20 · see citing works
Iron, Oxidative Stress and Health
Udipi, S., Ghugre, P., & Gokhale, C. (2012) · Oxidative Stress - Molecular Mechanisms and Biological Effects · doi:10.5772/34975 · Cited by 17 · see citing works
- Authors
- Kautz, L., Meynard, D., Monnier, A., Darnaud, V., Bouvet, R., Wang, R.-H., Deng, C., Vaulont, S., Mosser, J., Coppin, H., & Roth, M.-P.
- Affiliations
- Université Toulouse III - Paul Sabatier (FR)
- Centre National de la Recherche Scientifique (FR)
- Centre Hospitalier Universitaire de Rennes (FR)
- Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD;
- National Institutes of Health (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2008-08-15
- Volume
- 112
- Issue
- 4
- Pages
- 1503-1509
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2049917711
- Cited by
- 437
- References
- 12
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 10 · 2023: 23 · 2022: 24 · 2021: 21 · 2020: 21 · 2019: 26 · 2018: 18 · 2017: 28 · 2016: 25 · 2015: 20 · 2014: 26 · 2013: 31 · 2012: 27
- FWCI
- 24.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Association pour la Recherche sur le Cancer
- European Commission (LSHM-CT-2006-037296)
- Agence Nationale de la Recherche (ANR-05-MRAR-0031)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Micronutrient Interactions and Effects
- Keywords
- iron regulation, BMP/Smad signaling, Smad1/5/8 phosphorylation, BMP6, Smad7, Id1, ATOH8, hepcidin, SMAD4, iron deficiency, iron overload, hepatic gene expression, dietary iron
- MeSH terms
- Animals, Diet, Iron, Liver, Male, Phosphorylation, Transcription, Genetic, Signal Transduction, Mice, Knockout, Iron Overload, Bone Morphogenetic Proteins, Gene Expression Profiling, Active Transport, Cell Nucleus, Mice, Smad Proteins, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Smad1 Protein, Smad4 Protein, Smad5 Protein, Smad8 Protein, Smad7 Protein, Bone Morphogenetic Protein 6
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
