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J. Biol. Chem., Vol. 276, Issue 11, 7811-7819, March 16, 2001
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From the Considering that the development of
hepatic lesions related to iron overload diseases might be a result of
abnormally expressed hepatic genes, we searched for new genes
up-regulated under the condition of iron excess. By suppressive
subtractive hybridization performed between livers from carbonyl
iron-overloaded and control mice, we isolated a 225-base pair cDNA.
By Northern blot analysis, the corresponding mRNA was confirmed to
be overexpressed in livers of experimentally (carbonyl iron and
iron-dextran-treated mice) and spontaneously
( The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF297664, AF309489, and AF344185.
A New Mouse Liver-specific Gene, Encoding a Protein
Homologous to Human Antimicrobial Peptide Hepcidin, Is Overexpressed
during Iron Overload*
§,,,,¶,
, and
INSERM U522, CHRU Pontchaillou, Rennes,
¶ Laboratoire d'Anatomo-Pathologie B, CHRU Pontchaillou, Rennes,
and Service des Maladies du Foie, CHRU Pontchaillou,
35033 Rennes, France
2-microglobulin knockout mice) iron-overloaded mice. In addition, 2-microglobulin knockout mice fed
with a low iron content diet exhibited a decrease of hepatic mRNA
expression. The murine full-length cDNA was isolated and was found
to encode an 83-amino acid protein presenting a strong homology in its
C-terminal region to the human antimicrobial peptide hepcidin. In
addition, we cloned the corresponding rat and human orthologue
cDNAs. Both mouse and human genes named HEPC are
constituted of 3 exons and 2 introns and are located on chromosome 7 and 19, respectively, in close proximity to
USF2 gene. In mouse and human, HEPC mRNA was predominantly expressed in the liver. During both in
vivo and in vitro studies, HEPC mRNA expression
was enhanced in mouse hepatocytes under the effect of
lipopolysaccharide. Finally, to analyze the intracellular localization
of the predicted protein, we used the green fluorescent protein chimera
expression vectors. The murine green fluorescent protein-prohepcidin
protein was exclusively localized in the nucleus. When the putative
nuclear localization signal was deleted, the resulting protein was
addressed to the cytoplasm. Taken together, our data strongly suggest
that the product of the new liver-specific gene HEPC
might play a specific role during iron overload and exhibit additional
functions distinct from its antimicrobial activity.
*
This work was supported by La Ligue Contre le Cancer
(Comité d'Ille et Vilaine), BIOMED 2 Grant CE BMH4-CT97-2149,
the Ministère de la Recherche et de la Technologie,
l'Association pour la Recherche Contre le Cancer, and l'Association
Fer et Foie.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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L. Viatte, G. Nicolas, D.-Q. Lou, M. Bennoun, J.-C. Lesbordes-Brion, F. Canonne-Hergaux, K. Schonig, H. Bujard, A. Kahn, N. C. Andrews, et al. Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice Blood, April 1, 2006; 107(7): 2952 - 2958. [Abstract] [Full Text] [PDF]
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S. J. Wilkins, D. M. Frazer, K. N. Millard, G. D. McLaren, and G. J. Anderson Iron metabolism in the hemoglobin-deficit mouse: correlation of diferric transferrin with hepcidin expression Blood, February 15, 2006; 107(4): 1659 - 1664. [Abstract] [Full Text] [PDF]
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T. Ganz and E. Nemeth Iron imports. IV. Hepcidin and regulation of body iron metabolism Am J Physiol Gastrointest Liver Physiol, February 1, 2006; 290(2): G199 - G203. [Abstract] [Full Text] [PDF]
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T. Ganz Hepcidin and Its Role in Regulating Systemic Iron Metabolism Hematology, January 1, 2006; 2006(1): 29 - 35. [Abstract] [Full Text] [PDF]
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F. Canonne-Hergaux, A. Donovan, C. Delaby, H.-j. Wang, and P. Gros Comparative studies of duodenal and macrophage ferroportin proteins Am J Physiol Gastrointest Liver Physiol, January 1, 2006; 290(1): G156 - G163. [Abstract] [Full Text] [PDF]
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E. Nemeth, G. C. Preza, C.-L. Jung, J. Kaplan, A. J. Waring, and T. Ganz The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study Blood, January 1, 2006; 107(1): 328 - 333. [Abstract] [Full Text] [PDF]
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 D. S. Kalinowski and D. R. Richardson The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer Pharmacol. Rev., December 1, 2005; 57(4): 547 - 583. [Abstract] [Full Text] [PDF]
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E. Kemna, H. Tjalsma, C. Laarakkers, E. Nemeth, H. Willems, and D. Swinkels Novel urine hepcidin assay by mass spectrometry Blood, November 1, 2005; 106(9): 3268 - 3270. [Abstract] [Full Text] [PDF]
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J. J. Ravia, R. M. Stephen, F. K. Ghishan, and J. F. Collins Menkes Copper ATPase (Atp7a) Is a Novel Metal-responsive Gene in Rat Duodenum, and Immunoreactive Protein Is Present on Brush-border and Basolateral Membrane Domains J. Biol. Chem., October 28, 2005; 280(43): 36221 - 36227. [Abstract] [Full Text] [PDF]
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H. Makui, R. J. Soares, W. Jiang, M. Constante, and M. M. Santos Contribution of Hfe expression in macrophages to the regulation of hepatic hepcidin levels and iron loading Blood, September 15, 2005; 106(6): 2189 - 2195. [Abstract] [Full Text] [PDF]
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S. Rivera, E. Nemeth, V. Gabayan, M. A. Lopez, D. Farshidi, and T. Ganz Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs Blood, September 15, 2005; 106(6): 2196 - 2199. [Abstract] [Full Text] [PDF]
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 S. A. B. Knight, G. Vilaire, E. Lesuisse, and A. Dancis Iron Acquisition from Transferrin by Candida albicans Depends on the Reductive Pathway Infect. Immun., September 1, 2005; 73(9): 5482 - 5492. [Abstract] [Full Text] [PDF]
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E. Kemna, P. Pickkers, E. Nemeth, H. van der Hoeven, and D. Swinkels Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS Blood, September 1, 2005; 106(5): 1864 - 1866. [Abstract] [Full Text] [PDF]
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 X. Xu, H. L. Persson, and D. R. Richardson Molecular Pharmacology of the Interaction of Anthracyclines with Iron Mol. Pharmacol., August 1, 2005; 68(2): 261 - 271. [Abstract] [Full Text] [PDF]
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L. Detivaud, E. Nemeth, K. Boudjema, B. Turlin, M.-B. Troadec, P. Leroyer, M. Ropert, S. Jacquelinet, B. Courselaud, T. Ganz, et al. Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels, and hepatic function Blood, July 15, 2005; 106(2): 746 - 748. [Abstract] [Full Text] [PDF]
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D F Wallace, L Summerville, P E Lusby, and V N Subramaniam First phenotypic description of transferrin receptor 2 knockout mouse, and the role of hepcidin Gut, July 1, 2005; 54(7): 980 - 986. [Abstract] [Full Text] [PDF]
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 S.-L. Chen, M.-Y. Xu, X.-S. Ji, G.-C. Yu, and Y. Liu Cloning, Characterization, and Expression Analysis of Hepcidin Gene from Red Sea Bream (Chrysophrys major) Antimicrob. Agents Chemother., April 1, 2005; 49(4): 1608 - 1612. [Abstract] [Full Text] [PDF]
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X. Lauth, J. J. Babon, J. A. Stannard, S. Singh, V. Nizet, J. M. Carlberg, V. E. Ostland, M. W. Pennington, R. S. Norton, and M. E. Westerman Bass Hepcidin Synthesis, Solution Structure, Antimicrobial Activities and Synergism, and in Vivo Hepatic Response to Bacterial Infections J. Biol. Chem., March 11, 2005; 280(10): 9272 - 9282. [Abstract] [Full Text] [PDF]
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P. Ponka Iron is still hot: hepcidin keeps it ablaze Blood, February 15, 2005; 105(4): 1376 - 1377. [Full Text] [PDF]
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P. Lee, H. Peng, T. Gelbart, L. Wang, and E. Beutler Regulation of hepcidin transcription by interleukin-1 and interleukin-6 PNAS, February 8, 2005; 102(6): 1906 - 1910. [Abstract] [Full Text] [PDF]
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H Kulaksiz, F Theilig, S Bachmann, S G Gehrke, D Rost, A Janetzko, Y Cetin, and W Stremmel The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney J. Endocrinol., February 1, 2005; 184(2): 361 - 370. [Abstract] [Full Text] [PDF]
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R.J. MacIsaac, C. Tsalamandris, S. Panagiotopoulos, T.J. Smith, K.J. McNeill, G. Jerums, X Bai, D. Miao, J. Li, D. Goltzman, et al. Type 2 Diabetes: Absence of Proteinuria Does Not Preclude Loss of Renal Function: Nonalbuminuric Renal Insufficiency in Type 2 Diabetes. Diabetes Care 27: 195-200, 2004 J. Am. Soc. Nephrol., February 1, 2005; 16(2): 284 - 290. [Full Text] [PDF]
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M. D. Knutson, M. Oukka, L. M. Koss, F. Aydemir, and M. Wessling-Resnick Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin PNAS, February 1, 2005; 102(5): 1324 - 1328. [Abstract] [Full Text] [PDF]
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H. Kawabata, R. E. Fleming, D. Gui, S. Y. Moon, T. Saitoh, J. O'Kelly, Y. Umehara, Y. Wano, J. W. Said, and H. P. Koeffler Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis Blood, January 1, 2005; 105(1): 376 - 381. [Abstract] [Full Text] [PDF]
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M. B. Johnson and C. A. Enns Diferric transferrin regulates transferrin receptor 2 protein stability Blood, December 15, 2004; 104(13): 4287 - 4293. [Abstract] [Full Text] [PDF]
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J. Krijt, M. Vokurka, K.-T. Chang, and E. Necas Expression of Rgmc, the murine ortholog of hemojuvelin gene, is modulated by development and inflammation, but not by iron status or erythropoietin Blood, December 15, 2004; 104(13): 4308 - 4310. [Abstract] [Full Text] [PDF]
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 H. McGrath Jr and P. G. Rigby Hepcidin: inflammation's iron curtain Rheumatology, November 1, 2004; 43(11): 1323 - 1325. [Full Text] [PDF]
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