Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression
Abstract
Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.
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HFE, hemojuvelin, or TfR2 on the hepatocyte membrane impact hepcidin expression via the BMP-SMAD pathway.
“The latter is due to the fact, that several co-factors expressed on the hepatocyte cell membrane such as HFE, hemojuvelin (HJV) or TfR2 impact on hepcidin expression via the BMP-SMAD pathway (Babitt et al., 2006).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Babitt et al., 2006
Regulation of hepcidin by iron depends on the HJV and BMPR complex activating the SMAD signaling pathway.
“Regulation of hepcidin by iron depends on the hemojuvelin (HJV) and bone morphogenetic protein receptor (BMPR) complex activating the SMAD signaling pathway (Fig 3) [13–15].”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [13]
HJV is a BMP co-receptor that enhances iron signaling to hepcidin.
“HJV is a BMP co-receptor that enhances iron signaling to hepcidin (Babitt et al., 2006).”
From Pharmacological Targeting of the Hepcidin/Ferroportin Axis (2016) · cites this paper as Babitt et al., 2006
Bone morphogenetic protein-6 binds to a heterodimeric receptor complexed with hemojuvelin and matriptase-2, and stimulates hepcidin expression.
“BMP6 binds to a heterodimeric receptor complexed with hemojuvelin (HJV) and matriptase-2 (the gene product of TMPRSS6), and stimulates HAMP expression [66, 67].”
From Iron deficiency or anemia of inflammation?: Differential diagnosis and mechanisms of anemia of inflammation (2016) · cites this paper as [67]
BMP treatment is a potent stimulus for hepcidin expression both in cultured cells and in animals.
“Nonetheless, BMP treatment is a potent stimulus for hepcidin expression both in cultured cells 113,114,116,117 and in animals.”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [114]
Hemojuvelin acts as a BMP coreceptor to stimulate hepcidin transcription.
“They showed that hemojuvelin acts as a BMP coreceptor to stimulate hepcidin transcription.”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [114]
Activation of signaling through HFE, TFR1, TFR2, or HJV increases hepcidin transcription in a SMAD-dependent fashion.
“Activation of signaling through the hemochromatosis protein HFE, TFR1, TFR2, or hemojuvelin (HJV), which acts as a co-receptor for bone morphogenetic protein 6 (BMP6), increases hepcidin transcription in a SMAD-dependent fashion.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [200]
HFE2 is a BMP coreceptor, and its mutation suppresses BMP signaling.
“HFE2 is a BMP coreceptor, and its mutation suppresses BMP signaling (14).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
Hepcidin regulation through a signaling pathway involving hemojuvelin (HJV) and bone morphogenetic proteins (BMP) was identified.
“An alternative mechanism of hepcidin regulation through a signaling pathway involving hemojuvelin (HFE2, also known as HJV) and bone morphogenetic proteins (BMP) was recently identified (14).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
BMP can upregulate hepcidin in hepatocytes.
“This study showed that BMP could upregulate hepcidin in hepatocytes.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
Hepatocytes deficient in HFE2 had impaired hepcidin induction by BMP signaling.
“hepatocytes deficient in HFE2 had impaired hepcidin induction by BMP signaling (14).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
Overexpression of HFE2 enhanced hepcidin production.
“Overexpression of HFE2 enhanced hepcidin production.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
Smad4-knockout mice had lower levels of hepcidin and did not induce hepcidin in response to iron loading or IL-6 stimulation.
“Smad4-knockout mice had lower levels of hepcidin and did not induce hepcidin in response to iron loading or IL-6 stimulation (14).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
Downstream activation of Smad4 is required for BMP-mediated hepcidin upregulation.
“downstream activation of Smad4 was required for BMP-mediated hepcidin upregulation,”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
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BackgroundInfluentialRegulation of iron acquisition and storage: consequences for iron-linked disorders
De Domenico, I., McVey Ward, D., & Kaplan, J. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2295 · Cited by 464 · see citing works
Hepcidin and disorders of iron metabolism
Ganz, T., & Nemeth, E. (2011) · Annual Review of Medicine · doi:10.1146/annurev-med-050109-142444 · Cited by 466 · see citing works
Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance
Babitt, J. L., Huang, F. W., Xia, Y. Y., Sidis, Y., Andrews, N. C., & Lin, H. Y.-F. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31342 · Cited by 454 · see citing works
Regulation of the Iron Homeostatic Hormone Hepcidin
Sangkhae, V., & Nemeth, E. (2017) · Advances in Nutrition · doi:10.3945/an.116.013961 · Cited by 446 · see citing works
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“Recently, several factors were shown to regulate hepcidin, such as BMP/SMAD, STAT, and CEBP/α (Babitt et al., 2006; Babitt et al., 2007; Courselaud et al., 2002; Verga Falzacappa et al., 2007; Wang et al., 2005; Xia et al., 2008); whether these factors interact to regulate hepcidin transcription requires additional wo…”
BackgroundIron Homeostasis and the Inflammatory Response
Wessling-Resnick, M. (2010) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.012809.104804 · Cited by 480 · see citing works
“HJV is a coreceptor for bone morphogenic proteins (BMPs), and it has been demonstrated that the HJV/BMP complex regulates hepcidin expression (3).”
BackgroundIron uptake and metabolism in the new millennium
Dunn, L., Rahmanto, Y. S., & Richardson, D. R. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.12.003 · Cited by 419 · see citing works
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Iron Sequestration and Anemia of Inflammation
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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
Oxidative Stress and Iron Homeostasis: Mechanistic and Health Aspects
Galaris, D., & Pantopoulos, K. (2008) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408360701713104 · Cited by 352 · see citing works
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Molecular control of iron transport
Ganz, T. (2007) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006070802 · Cited by 353 · see citing works
Targeting iron metabolism in drug discovery and delivery
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Hypoxic regulation of erythropoiesis and iron metabolism
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“protein-6 (BMP6) and induces hepcidin transcription in a SMAD-dependent fashion (4, 8, 103).”
BackgroundHypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis
Liu, Q., Davidoff, O., Niss, K., & Haase, V. H. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63924 · Cited by 328 · see citing works
“…transferrin receptor 1 (TRFC) and transferrin receptor 2 (TFR2) (2, 11, 12), or hemojuvelin (HJV), which acts as a coreceptor for bone morphogenetic protein 6 (BMP6), increases hepcidin expression in a mothers against decapen-taplegic homolog–dependent (SMAD-dependent) fashion (13–15).”
Iron metabolism in the anemia of chronic disease
Weiss, G. (2009) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2008.08.006 · Cited by 322 · see citing works
“HIF1-α can activate furin production and in turn induces the release of soluble hemojuvelin (sHJV) which suppresses hepcidin production via inhibition of bone morphogenic proteins 2, 4 (BMP2,4) [214–217].”
BackgroundER Stress Controls Iron Metabolism Through Induction of Hepcidin
Vecchi, C., Montosi, G., Zhang, K., Lamberti, I., Duncan, S. A., Kaufman, R. J., & Pietrangelo, A. (2009) · Science · doi:10.1126/science.1176639 · Cited by 310 · see citing works
Anderson, G. J., & Vulpe, C. D. (2009) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-009-0051-1 · Cited by 317 · see citing works
Hepcidin: from discovery to differential diagnosis
Kemna, E., Tjalsma, H., Willems, H. L., & Swinkels, D. W. (2007) · Haematologica · doi:10.3324/haematol.11705 · Cited by 313 · see citing works
STAT3 Is Required for IL-6-gp130–Dependent Activation of Hepcidin In Vivo
Pietrangelo, A., Dierssen, U., Valli, L., Garuti, C., Rump, A., Corradini, E., Ernst, M., Klein, C., & Trautwein, C. (2007) · Gastroenterology · doi:10.1053/j.gastro.2006.10.018 · Cited by 315 · see citing works
Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis
Silvestri, L., Pagani, A., & Camaschella, C. (2008) · Blood · doi:10.1182/blood-2007-07-100677 · Cited by 311 · see citing works
Gardenghi, S., Marongiu, M. F., Ramos, P., Guy, E. C., Breda, L., Chadburn, A., Liu, Y.-F., Amariglio, N., Rechavi, G., Rachmilewitz, E. A., et al. (2007) · Blood · doi:10.1182/blood-2006-09-048868 · Cited by 307 · see citing works
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Iron metabolism: pathophysiology and pharmacology
Roemhild, K., von Maltzahn, F., Weiskirchen, R., Knüchel, R., von Stillfried, S. F., & Lammers, T. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.05.001 · Cited by 315 · see citing works
The Role of Iron Regulation in Immunometabolism and Immune-Related Disease
Cronin, S. J. F., Woolf, C. J., Weiss, G., & Penninger, J. M. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00116 · Cited by 299 · see citing works
“The latter is due to the fact, that several co-factors expressed on the hepatocyte cell membrane such as HFE, hemojuvelin (HJV) or TfR2 impact on hepcidin expression via the BMP-SMAD pathway (Babitt et al., 2006).”
BackgroundBMP signalling: agony and antagony in the family
Brazil, D. P., Church, R. H., Surae, S., Godson, C., & Martin, F. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.12.004 · Cited by 306 · see citing works
Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis
Folgueras, A. R., de Lara, F. M., Pendás, A. M., Garabaya, C., Rodríguez, F. J., Astudillo, A., Bernal, T., Cabanillas, R., López-Otı́n, C., & Velasco, G. (2008) · Blood · doi:10.1182/blood-2008-04-149773 · Cited by 300 · 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
“The activated receptors induce the phosphorylation of cytosolic SMADs 1, 5 and 8 [71,73,74].”
BackgroundEvstatiev, R., & Gasché, C. (2011) · Gut · doi:10.1136/gut.2010.214312 · Cited by 292 · see citing works
“The R-SMAD bind to the common mediator SMAD 4 and ultimately act as a transcription factor to trigger hepcidin transcription.(98) Two highly conserved BMPresponsive elements are located in the hepcidin”
BackgroundHepcidin 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
Macrophages and Systemic Iron Homeostasis
Ganz, T. (2012) · Journal of Innate Immunity · doi:10.1159/000336423 · Cited by 281 · see citing works
Rouault, T. A., & Cooperman, S. (2006) · Seminars in Pediatric Neurology · doi:10.1016/j.spen.2006.08.002 · Cited by 280 · 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
Importance of Iron Chelation in Free Radical-Induced Oxidative Stress and Human Disease
Jomová, K., & Valko, M. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211798072463 · Cited by 271 · see citing works
BMP signaling in vascular diseases
Cai, J., Pardali, E., Sánchez‐Duffhues, G., & ten Dijke, P. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.04.030 · Cited by 269 · see citing works
“Family members of RGM, RGMa, RGMb (DRAGON) and RGMc, were shown to be implicated in BMP signaling (29-31).”
BackgroundNishina, S., Hino, K., Korenaga, M., Vecchi, C., Pietrangelo, A., Mizukami, Y., Furutani, T., Sakai, A., Okuda, M., Hidaka, I., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2007.10.011 · Cited by 259 · see citing works
Differential regulation of myeloid leukemias by the bone marrow microenvironment
Krause, D., Fulzele, K. S., Catic, A., Sun, C.-C., Dombkowski, D., Hurley, M. P., Lezeau, S., Attar, E. C., Wu, J. Y., Lin, H. Y., et al. (2012) · Nature Medicine · doi:10.1038/nm.3364 · Cited by 72 · see citing works
“For the daily subcutaneous injections (intermittent dosing regimen), we administered human PTH (1-34) or saline at 80 μg per kg body weight per day.”
MethodHepcidin and Its Role in Regulating Systemic Iron Metabolism
Ganz, T. (2006) · Hematology · doi:10.1182/asheducation-2006.1.29 · Cited by 260 · see citing works
The emerging role of TGF-β superfamily coreceptors in cancer
Bernabéu, C., López-Novoa, J. M., & Quintanilla, M. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.07.003 · Cited by 254 · see citing works
The Regulation of Iron Absorption and Homeostasis.
Wallace, D. F. (2016) · PubMed Central · Cited by 255 · see citing works
NCOA4 deficiency impairs systemic iron homeostasis
Bellelli, R., Federico, G., Matte’, A., Colecchia, D., Iolascon, A., Chiariello, M., Santoro, M., De Franceschi, L., & Carlomagno, F. (2016) · Cell Reports · doi:10.1016/j.celrep.2015.12.065 · Cited by 248 · see citing works
Hepcidin in Human Iron Disorders: Diagnostic Implications
Kroot, J. J., Tjalsma, H., Fleming, R. E., & Swinkels, D. W. (2011) · Clinical Chemistry · doi:10.1373/clinchem.2009.140053 · Cited by 246 · see citing works
Brain iron metabolism and its perturbation in neurological diseases
Crichton, R. R., Dexter, D. T., & Ward, R. J. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0470-z · Cited by 246 · see citing works
“... a- and b-secretases is modulated by furin, a member of the subtilisin-like proprotein convertase family which catalyses the cleavage of precursor proteins into their biologically active forms (Seidah et al. 1994) Furin is also involved in modulation of systemic iron homeostasis through the production of soluble ha…”
BackgroundThe liver-specific microRNA miR-122 controls systemic iron homeostasis in mice
Castoldi, M., Spasić, M. V., Altamura, S., Elmén, J., Lindow, M., Kiss, J., Stolte, J., Sparla, R., D’Alessandro, L. A., Klingmüller, U., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44883 · Cited by 246 · see citing works
“Elevated expression of Hfe, Hjv, and Bmpr1a would be expected to stimulate the Bmp/Smad signaling pathway in mice (44).”
BackgroundHepcidin and Anemia: A Tight Relationship
Pagani, A., Nai, A., Silvestri, L., & Camaschella, C. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01294 · Cited by 256 · see citing works
The long history of iron in the Universe and in health and disease
Sheftel, A. D., Mason, A. B., & Ponka, P. (2011) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.08.002 · Cited by 234 · see citing works
Molecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD
Babitt, J. L., & Lin, H. Y.-F. (2010) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2009.12.030 · Cited by 236 · see citing works
The Spectrum of Achalasia: Lessons From Studies of Pathophysiology and High-Resolution Manometry
Kahrilas, P. J., & Boeckxstaens, G. E. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.08.038 · Cited by 234 · see citing works
Song, S.-N. J., Tomosugi, N., Kawabata, H., Ishikawa, T., Nishikawa, T., & Yoshizaki, K. (2010) · Blood · doi:10.1182/blood-2010-03-271791 · Cited by 228 · see citing works
Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice
Guo, S., Casu, C., Gardenghi, S., Booten, S. L., Aghajan, M., Peralta, R. Q., Watt, A., Freier, S., Monia, B. P., & Rivella, S. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66969 · Cited by 224 · see citing works
“At the molecular level, Hamp expression is controlled by the activation of the SMAD1,5,8/SMAD4 complex, which in turn is triggered by the association between the BMP6 ligand, whose expression is proportional to intracellular hepatic iron concentrations, and the BMP-receptor complex (10–12).”
The role of iron homeostasis in remodeling immune function and regulating inflammatory disease
Mu, Q., Chen, L., Gao, X., Shen, S., Sheng, W., Min, J., & Wang, F. (2021) · 中国科学通报：英文版 · doi:10.1016/j.scib.2021.02.010 · Cited by 226 · see citing works
Xia, Y. Y., Babitt, J. L., Sidis, Y., Chung, R. T., & Lin, H. Y.-F. (2008) · Blood · doi:10.1182/blood-2007-09-111567 · Cited by 223 · see citing works
Targeting BMP signalling in cardiovascular disease and anaemia
Morrell, N. W., Bloch, D. B., ten Dijke, P., Goumans, M., Hata, A., Smith, J., Yu, P. B., & Bloch, K. D. (2015) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2015.156 · Cited by 223 · see citing works
“181 Ferroportin is the sole molecule responsible for exporting iron from intracel‑ lular stores within intestinal epithelial cells, hepatocytes, and macrophages into the circulation.”
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
Fraenkel, P. G. (2016) · Medical Clinics of North America · doi:10.1016/j.mcna.2016.09.005 · Cited by 223 · see citing works
Anderson, E. R., & Shah, Y. M. (2012) · Comprehensive physiology · doi:10.1002/cphy.c120016 · Cited by 249 · see citing works
Hemochromatosis: An endocrine liver disease
Pietrangelo, A. (2007) · Hepatology · doi:10.1002/hep.21886 · Cited by 212 · see citing works
Lawen, A., & Lane, D. J. R. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4271 · Cited by 217 · see citing works
“Importantly, the GPI-linked form of HJV appears to function as a coreceptor for BMP6, and facilitates the BMP6-dependent upregulation of hepcidin expression (13).”
Hepcidin and Host Defense against Infectious Diseases
Michels, K., Nemeth, E., Ganz, T., & Mehrad, B. (2015) · PLOS Pathogens · doi:10.1371/journal.ppat.1004998 · Cited by 205 · see citing works
“Regulation of hepcidin by iron depends on the hemojuvelin (HJV) and bone morphogenetic protein receptor (BMPR) complex activating the SMAD signaling pathway (Fig 3) [13–15].”
BackgroundOstroff, R. M., Bigbee, W. L., Franklin, W. A., Gold, L., Mehan, M., Miller, Y. E., Pass, H. I., Rom, W. N., Siegfried, J. M., Stewart, A., et al. (2010) · Nature Precedings · doi:10.1371/journal.pone.0015003 · Cited by 213 · see citing works
“Unlike the membrane bound form, soluble RGM-C inhibits hepcidin expression [50,51].”
BackgroundEndothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice
Canali, S., Zumbrennen‐Bullough, K. B., Core, A. B., Wang, C., Nairz, M., Bouley, R., Świrski, F. K., & Babitt, J. L. (2016) · Blood · doi:10.1182/blood-2016-06-721571 · Cited by 214 · see citing works
Zhao, N., Zhang, A., & Enns, C. A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67225 · Cited by 210 · see citing works
“In the liver, HJV is exclusively expressed in hepatocytes (16, 26) and acts as a coreceptor for BMP6 to induce hepcidin expression via the BMP signaling pathway (11, 20, 27), presumably by using ActRIIA in combination with either ALK2 or ALK3 (28).”
Biochemistry and Biology of GDF11 and Myostatin
Walker, R. G., Poggioli, T., Katsimpardi, L., Buchanan, S. M., Oh, J., Wattrus, S. J., Heidecker, B., Fong, Y. W., Rubin, L. L., Ganz, P., et al. (2016) · Circulation Research · doi:10.1161/circresaha.116.308391 · Cited by 210 · see citing works
Wallace, D. F., Summerville, L., Crampton, E. M., Frazer, D. M., Anderson, G. J., & Subramaniam, V. N. (2009) · Hepatology · doi:10.1002/hep.23198 · Cited by 206 · see citing works
D’Alessio, F., Hentze, M. W., & Muckenthaler, M. U. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.06.015 · Cited by 200 · see citing works
“While HJV is a BMP co-receptor that enhances BMP/SMAD signaling [24], the mechanism(s) of how HFE and TfR2 contribute to the control of hepcidin activation remain(s) elusive.”
BackgroundMethodInfluentialHepcidin regulation in prostate and its disruption in prostate cancer
Tesfay, L., Clausen, K. A., Kim, J. W., Hegde, P., Wang, X., Miller, L. D., Deng, Z., Blanchette, N., Arvedson, T., Miranti, C. K., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2465 · Cited by 186 · see citing works
“1 mg TCF/LEF firefly luciferase (Qiagen) or hepcidin luciferase construct (17) and constitutively active Renilla luciferase.”
BackgroundGinzburg, Y., & Rivella, S. (2011) · Blood · doi:10.1182/blood-2011-03-283614 · Cited by 201 · see citing works
Iron Regulation: Macrophages in Control
Sukhbaatar, N., & Weichhart, T. (2018) · Pharmaceuticals · doi:10.3390/ph11040137 · Cited by 201 · see citing works
“On the contrary, pathological hepcidin excess caused by inflammatory disorders induces hypoferremia, anemia of inflammation, or anemia of chronic disease [31,63,64].”
Background
- Authors
- 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., Andrews, N. C., & Lin, H. Y.
- Affiliations
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Lin, Herbert Y
- ORCID
- Venue
- Nature Genetics
- Published
- 2006-04-09
- Volume
- 38
- Issue
- 5
- Pages
- 531-539
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2050833520
- Cited by
- 1,026
- References
- 52
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 21 · 2023: 22 · 2022: 21 · 2021: 54 · 2020: 35 · 2019: 39 · 2018: 39 · 2017: 50 · 2016: 44 · 2015: 50 · 2014: 58 · 2013: 62 · 2012: 67
- FWCI
- 49.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL07623, T32HL007623)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-71837, R01DK066373, DK-69533, K08DK075846, R01DK071837, F32DK068997, R01DK069533)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Micronutrient Interactions and Effects
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- hemojuvelin, hepcidin, BMP signaling, iron homeostasis, hemochromatosis, RGMa, dragons, hepatocytes, iron overload, anemia
- MeSH terms
- Hemochromatosis Protein, Amino Acid Sequence, Animals, Gene Expression Regulation, Cricetinae, Humans, Liver, Membrane Proteins, Molecular Sequence Data, Mutation, Signal Transduction, Polymerase Chain Reaction, Transforming Growth Factor beta, CHO Cells, Bone Morphogenetic Proteins, Antimicrobial Cationic Peptides, Bone Morphogenetic Protein 2, GPI-Linked Proteins, Hepcidins
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