Quantitative evaluation of expression of iron-metabolism genes in ceruloplasmin-deficient mice

Yamamoto, Kanji; Yoshida, Katsumi; Miyagoe, Yuko; Ishikawa, Aki; Hanaoka, Kazunori; Nomoto, Shozo; Kaneko, Kazuma; Ikeda, Shu‐ichi; Takeda, Shin’ichi

doi:10.1016/s0925-4439(02)00165-5

Cited by 49 publications

(54 citation statements)

References 37 publications

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“…All of these observations are consistent with the model that copper status can modulate iron release due to the metal's regulation of FPN1 gene expression. This model is also consistent with the observations that copper-deficient rodents, which have ironloaded but copper-depleted livers, display profound microcytic anemia (5, 6), whereas Cp Ϫ/Ϫ mice and ceruloplasmindeficient Long-Evans Cinnamon rats, which have hepatic iron-and copper-loading, suffer only mild hematological disturbances (10,11,40).…”

Section: Discussionsupporting

confidence: 89%

“…Consistent with this model, ceruloplasmin knockout mice store excess iron in liver and the reticuloendothelial system (10). However, the absence of ceruloplasmin activity does not fully explain the function of copper in iron release because these animals display only very mild iron deficiency anemia (11). Moreover, aceruloplasminemic patients who inherit loss-of-function mutations in the ceruloplasmin gene are also only slightly anemic (12).…”

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confidence: 86%

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Copper-induced ferroportin-1 expression in J774 macrophages is associated with increased iron efflux

Chung

Haile²,

Wessling‐Resnick

2004

Proc. Natl. Acad. Sci. U.S.A.

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Copper is known to play a role in iron recycling from macrophages. To examine whether cellular copper status affects expression of the iron exporter ferroportin-1 (FPN1), J774 macrophage cells were exposed to 10 -100 M CuSO4 for up to 20 h. Copper treatment significantly increased FPN1 mRNA in a dose-and time-dependent manner. After 20 h, 100 M CuSO4 up-regulated FPN1 transcript levels Ϸ13-fold compared to untreated controls. Induction was detected 8 h after copper treatment was initiated and markedly increased thereafter. A corresponding increase in FPN1 protein levels was observed upon copper treatment. Induction of J774 cell FPN1 expression by copper was also associated with a dosedependent increase in 59 Fe release after erythrophagocytosis of labeled red blood cells. Thus, a previously uncharacterized role for copper in the regulation of macrophage iron recycling is suggested by the induction of FPN1 gene expression and iron efflux by this metal.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 86%

Copper-induced ferroportin-1 expression in J774 macrophages is associated with increased iron efflux

Chung

Haile²,

Wessling‐Resnick

2004

Proc. Natl. Acad. Sci. U.S.A.

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“…21,22 The primer pairs used for quantification of specific mRNAs are listed in Table 1 and were in part described previously. [23][24][25] Liver iron analysis Total iron in the liver tissues was determined by flame atomic absorption spectroscopy under alkaline conditions on a Varian SpectrAA220 spectrometer (Varian, Zug, Switzerland) following solubilization by tetramethylammonium hydroxide. 26…”

Section: Quantitative Reverse Transcriptase-polymerase Chain Reactionmentioning

confidence: 99%

“…21,22 The primer pairs used for quantification of specific mRNAs are listed in Table 1 and were in part described previously. [23][24][25] …”

Section: Quantitative Reverse Transcriptase-polymerase Chain Reactionmentioning

confidence: 99%

Normal erythropoiesis but severe polyposis and bleeding anemia in Smad4-deficient mice

Pan

Schomber

Kalberer

et al. 2007

Blood

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The tumor suppressor Smad4 mediates signaling by the transforming growth factor beta (TGF-␤) superfamily of ligands. Previous studies showed that several TGF-␤ family members exert important functions in hematopoiesis. Here, we studied the role of Smad4 in adult murine hematopoiesis using the inducible MxCre/loxP system. Mice with homozygous Smad4 deletion (Smad4 ⌬/⌬ ) developed severe anemia 6 to 8 weeks after induction (mean hemoglobin level 70 g/L). The anemia was not transplantable, as wild-type mice reconstituted with Smad4 ⌬/⌬ bone marrow cells had normal peripheral blood counts. These mice did not develop an inflammatory disease typical for mice deficient in TGF-␤ receptors I and II, suggesting that the suppression of inflammation by TGF-␤ is Smad4 independent. The same results were obtained when Smad4 alleles were deleted selectively in hematopoietic cells using the VavCre transgenic mice. In contrast, lethally irradiated Smad4 ⌬/⌬ mice that received wild-type bone marrow cells developed anemia similar to Smad4 ⌬/⌬ mice that did not receive a transplant. Liver iron stores were decreased and blood was present in stool, indicating that the anemia was due to blood loss. Multiple polyps in stomach and colon represent a likely source of the bleeding. We conclude that Smad4 is not required for adult erythropoiesis and that anemia is solely the consequence of blood loss. IntroductionThe members of the transforming growth factor beta (TGF-␤) superfamily of ligands modulate cell proliferation, differentiation, apoptosis, adhesion, and cell migration. 1 These ligands, including TGF-␤, activins, and bone morphogenetic proteins (BMPs), bind cell-surface receptors, classified as type I and II receptors, that contain an intracellular serine/threonine protein kinase domain. Upon ligand activation, the type II and type I receptors form an active ligand-receptor complex that phosphorylates members of the Small mutants (Caenorhabditis elegans) and mothers against the decapentaplegic homolog (Smad) family of proteins. The Smad family members that directly interact with the receptors are called receptor Smads (R-Smad). The type I receptors for TGF-␤, activin, nodal, and myostatin phosphorylate R-Smad2 and 3, whereas the BMPs phosphorylate R-Smad1, 5, and 8. The R-Smads associate with Smad4, also called common partner Smad (co-Smad), and as a complex enter the nucleus to regulate transcription. Smad6 and Smad7 TGF-␤ inhibit signaling through multiple mechanisms and are called inhibitory Smads (I-Smad). 2 Hematopoiesis is a tightly balanced process consisting of cell self-renewal, differentiation, and apoptosis of hematopoietic cells. The effects of TGF-␤ signaling on hematopoiesis are cell and context specific. TGF-␤1 has an inhibitory function in early expansion of committed hematopoietic precursors, 3 and BMP4 is implicated in mesoderm induction and hematopoietic commitment during embryogenesis. 4 Mice deficient for TGF-␤1 die 3 to 4 weeks after birth due to an inflammatory syndrome, 5,6 whereas the knockouts of the TGF-␤...

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“…However, Williams and co-workers (46) showed that the ferroxidase activity of Cp varies widely between species, being lowest in the rat and 10-fold higher in swine, which led the authors to conclude that this action may not be the major function of Cp but that it only enhances the export of iron. Certainly, intact Cp is necessary for the export of iron, because iron accumulated in the liver of individuals with aceruloplasminemia and in Cp knockout mice (18,47).…”

mentioning

confidence: 99%

Copper deficiency increases iron absorption in the rat

Thomas

Oates

2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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Release of iron from enterocytes and hepatocytes is thought to require the copper-dependent ferroxidase activity of hephaestin (Hp) and ceruloplasmin (Cp), respectively. In swine, copper deficiency (CD) impairs iron absorption, but whether this occurs in rats is unclear. By feeding a diet deficient in copper, CD was produced, as evidenced by the loss of copper-dependent plasma ferroxidase I activity, and in enterocytes, CD reduced copper levels and copper-dependent oxidase activity. Hematocrit was reduced, and liver iron was doubled. CD reduced duodenal mucosal iron and ferritin, whereas CD increased iron absorption. Duodenal mucosal DMT1-IRE and ferroportin1 expression remained constant with CD. When absorption in CD rats was compared with that seen normally and in iron-deficient anemic animals, strong correlations were found among mucosal iron, ferritin, and iron absorption, suggesting that the level of iron absorption was appropriate given that the erythroid and stores stimulators of iron absorption are opposed in CD. Because CD reduced the activity of Cp, as evidenced by copper-dependent plasma ferroxidase I activity and hepatocyte iron accumulation, but iron absorption increased, it is unlikely that the ferroxidase activity of Hp is important and suggests another function for this protein in the export of iron from the enterocyte during iron absorption. Also, the copper-dependent ferroxidase activity of Cp does not appear important for iron efflux from macrophages, because Kupffer cells of the liver and nonheme iron levels of the spleen were normal during copper deficiency, suggesting another role for Cp in these cells.

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Quantitative evaluation of expression of iron-metabolism genes in ceruloplasmin-deficient mice

Cited by 49 publications

References 37 publications

Copper-induced ferroportin-1 expression in J774 macrophages is associated with increased iron efflux

Copper-induced ferroportin-1 expression in J774 macrophages is associated with increased iron efflux

Normal erythropoiesis but severe polyposis and bleeding anemia in Smad4-deficient mice

Copper deficiency increases iron absorption in the rat

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