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RED CELLS
From the Division of Hematology/Oncology, Department of
Medicine, Burns and Allen Research Institute, Cedars-Sinai Medical
Center, University of California Los Angeles School of Medicine;
and Department of Hematology/ Immunology, Kanazawa
Medical University, Uchinada-machi, Ishikawa-ken, Japan.
Complementary and genomic DNA for the murine transferrin receptor 2 (TfR2) were cloned and mapped to chromosome 5. Northern blot analysis
showed that high levels of expression of murine TfR2 occurred in the
liver, whereas expression of TfR1 in the liver was relatively low.
During liver development, TfR2 was up-regulated and TfR1 was
down-regulated. During erythrocytic differentiation of murine
erythroleukemia (MEL) cells induced by dimethylsulfoxide, expression of
TfR1 increased, whereas TfR2 decreased. In MEL cells, expression of
TfR1 was induced by desferrioxamine, an iron chelator, and it was
reduced by ferric nitrate. In contrast, levels of TfR2 were not
affected by the cellular iron status. Reporter assay showed that
GATA-1, an erythroid-specific transcription factor essential for
erythrocytic differentiation at relatively early stages, enhanced TfR2
promoter activity. Interestingly, FOG-1, a cofactor of GATA-1 required
for erythrocyte maturation, repressed the enhancement of the activity
by GATA-1. Also, CCAAT-enhancer binding protein, which is abundant in
liver, enhanced the promoter activity. Thus, tissue distribution of
TfR2 was consistent with the reporter assays. Expression profiles of
TfR2 were different from those of TfR1, suggesting unique functions for
TfR2, which may be involved in iron metabolism, hepatocyte function,
and erythrocytic differentiation.
(Blood. 2001;98:1949-1954) Iron, one of the essential elements of life, is
carried by transferrin (Tf) in the serum and absorbed by the cells
through transferrin receptor (TfR1)-mediated mechanisms.1
Diferric Tf in the serum binds to TfR1 on the cell surface, followed by endocytosis of the receptor-ligand complex. HFE is an atypical major
histocompatibility complex (MHC) class I molecule that can form a
complex with TfR1 on the cell surface and interfere with binding of Tf
to TfR1.2-4 Mutations of HFE are thought to be related to
hereditary hemochromatosis. After internalization of the Tf-TfR1
complex, iron is released from the Tf-TfR1 complex in the endosome and
is transported to the cytoplasm and mitochondria by DMT1/Nramp2, a
transmembrane iron transporter.5-8
Recently, we cloned human TfR2, another transferrin receptor gene. Two
alternatively spliced forms of human TfR2 transcripts were identified:
In this paper, we describe the molecular cloning, chromosomal mapping,
and characterization of expression of murine TfR2. Tissue distribution
of TfR2 was clearly different from that of TfR1. We compared expression
profiles of TfR1 and TfR2 mRNAs in murine erythroleukemia (MEL) cells
in response to iron status and during their erythrocytic
differentiation. We also examined the regulation of the murine TfR2
promoter by transcription factors that may be related to its
tissue-specific expression. These results will help to elucidate the
physiologic function of TfR2.
Cell culture and differentiation
Molecular cloning of complementary and genomic DNA of
murine TfR2
Chromosomal mapping T31 Mouse Radiation Hybrid Panel, RH04.02 (Research Genetics), was used to determine the chromosomal location of the TfR2 gene, as described previously.15 The primers 5'-TGGTAGACCACCTGCGGATG-3' and 5'-AGGGAGAAAGGAGAATCACGTGG-3' amplified a 227-bp fragment. The polymerase chain reaction (PCR) products were subjected to electrophoresis, Southern blotting, and hybridization with a 32P-labeled probe of murine TfR2. The results were analyzed by the Jackson Laboratory Mapping Panels (www.http://jax.org/resources/documents/cmdata).Reverse transcriptase-PCR and Northern blot analyses Reverse transcriptase-PCR (RT-PCR) and Northern blot analyses were performed essentially as described previously.9 As a template of RT-PCR, Mouse Multiple Tissue cDNA Panel I (Clontech) was used. To amplify murine TfR2 cDNA, we used primers 5'-TGCACAAGATGCTGCGAGGT-3' and 5'-GTTCCGCTCCGAGCTGTAA-3'. Conditions for amplification were 32 cycles of 94°C for 30 seconds, 56°C for 40 seconds, and 72°C for 1 minute. As a control, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was amplified in a separate reaction for 24 cycles using primers coming with the cDNA panel. The products were subjected to electrophoresis, Southern blotting, hybridization with radiolabeled probes, and autoradiography. For Northern blots, various murine tissues were prepared from C3H mice, and total RNA was extracted. Intestinal mucosa was prepared by scraping the inner surface of small intestines. As probes, 0.5 kb of the murine TfR1, the 3' part of 1.4-kb murine TfR2, and 0.9-kb murine GAPDH cDNA fragments were used. In some experiments, relative expression levels of TfRs were calculated by an image analyzer, standardized by the expression levels of GAPDH, and shown as bar graphs.Reporter assay Reporter constructs pGL-mTfR2-pro-0.3 kb, -0.4 kb, -1.0 kb, and -2.1 kb were created by subcloning fragments of the murine TfR2 promoter from the transcription starting site to either the 0.3-kb upstream McsI site, the nucleotide at 392, the
approximately 1-kb upstream BglII site, or the 2.1-kb
upstream NheI site, respectively, into pGL3-basic vector
plasmid (Promega, Madison, WI). Expression plasmids for GATA-1 and
FOG-1, pXM-GATA1, and pMT2-FOG were kindly provided by Drs A. Tsang and
S. Orkin.16,17 An expression plasmid for murine
CCAAT/enhancer binding protein (C/EBP- ) was provided by Dr
Xanthropoulos.18 An expression plasmid for erythroid
Kruppel-like factor (EKLF) was created as follows. The complete coding
sequence of EKLF was amplified by RT-PCR using K562 cDNA as template,
tagged with FLAG at the 5'-end, and subcloned into pcDNA3.1(+)
(Invitrogen, Carlsbad, CA). Expression of EKLF protein at a proper size
was confirmed by Western blotting after transient transfection of NIH-3T3 cells. NIH-3T3 cells were transfected by GenePorter system (Gene Therapy Systems, San Diego, CA) with either empty pGL3-basic or
pGL-mTfR2 promoter plasmids together with expression plasmids for
GATA-1, FOG, EKLF, and/or C/EBP-. To normalize the transfection efficiency, we cotransfected pCMV · SPORT- Gal (Life
Technologies). Cells were harvested after 60 hours, and luciferase and
-galactosidase activities were measured with a luminometer and with
the -galactosidase Enzyme Assay System (Promega), respectively.
Homology between human and murine TfR2 Approximately 2.8 kb of cDNA sequences for murine TfR2 was obtained from the cDNA library of MEL cells by assembling sequences of 5' and 3' rapid amplification of cDNA ends (RACE) products (GenBank accession number AF207741). As Fleming et al19 reported previously analyzing an EST clone, putative amino acid sequences of murine TfR2 were similar to those of human TfR2-,
sharing 85% identical and 92% similar amino acids. Murine TfR2 had a
putative internalization motif, YRRV, and a transmembrane domain (amino acids 78-102) consisting of a hydrophobic amino acid stretch. We also
cloned genomic DNAs including the promoter region (GenBank accession
number AF207742). When we compared this genomic sequence with the human
counterpart, promoter sequences from 360 to 0 were considerably
conserved (Figure 1). Both human and
murine TfR2 promoters contained 2 typical GATA-1 (an erythroid-specific transcription factor) consensus sequences, (W)GATA(R) at 52 to 57
and 23 to 19 for mouse, and 61 to 56 and 26 to 22 for man,
respectively (underlined in Figure 1). Also, putative C/EBP binding sites, a doublet of CAAT at around 240, and a CCAAT sequence in the reverse direction at around 190, were seen in both human and
murine TfR2 promoters (double underlines). In addition, several CACCC
sequences, which can be EKLF consensus sequences, were found both in
the human and murine TfR2 promoters within the upstream 1 kb from the
transcription starting sites (GenBank accession number AF207742). We
also found an interesting palindrome structure at 978 to 997,
CAGTTTCCCAGGGAAACTG, although its meaning and function are unknown. Our
cDNA sequence of murine TfR2 is identical to that reported by Fleming
et al19 except for the 5' portion; Fleming's sequence has
an additional noncoding exon before our exon 1 (exon 1a, 248 to 189
base; Figure 1) and lacks 17 nucleotides at the 5' portion of
our exon 1. Because of these differences, putative GATA-1 and C/EBP
sites are located in intron 1 and exon 1a of Fleming's sequences,
respectively.
Alternative forms of murine TfR2 transcripts When we amplified the putative coding sequence of murine TfR2 by RT-PCR, we obtained clones of 3 different lengths (Figure 2). The sequences of the middle-length form (type 1 in Figure 2) were identical to clones that we obtained from RACE; thus, this is probably the dominant form of murine TfR2 transcripts. The longer clone (type 2 in Figure 2) had an additional sequence between exons 5 and 6, which was the sequence of intron 5, and the shorter clone (type 3) had a deletion of exon 2. The former splicing variation caused a 14-amino acid addition after amino acid 237, followed by a stop codon (VRFPGWGAHHVLIGX). The latter caused an in-frame deletion of amino acids 12 to 93, which includes most of the putative intracellular and part of the transmembrane domains. Thus, the cDNA library from MEL cells contains at least 3 different lengths of TfR2 transcripts. We did not find murine TfR2 clones corresponding to the-form of human TfR2 when we performed
5'-RACE using the MEL cDNA library. However, we did see at least 3 bands with different sizes on Northern analysis when we used the 1.4-kb
3'-portion of the TfR2 cDNA as a probe, indicating the presence of
alternative forms of murine TfR2 transcripts (Figure
3B). These 3 bands, however, do not
correspond to the 3 forms shown in Figure 2 because the sizes of the
latter 3 forms are too close to separate in Northern blots (type 1, 2.8 kb; type 2, 2.9 kb; type 3, 2.5 kb). On the other hand, when we used
the 1.4-kb 5'-portion of TfR2 cDNA as a probe, only one band with the
size of approximately 2.9 kb was observed. Probably variations occur in
the 5'-portion of the transcripts coding for TfR2, and those
corresponding to the -form may exist although they might not be
abundant, explaining why we could not isolate them.
Chromosomal mapping The radiation hybrid panel analysis revealed that the murine TfR2 was on the distal end of chromosome 5, between the D5Mit168 and D5Mit326 markers. This location is syntenic to human chromosome 7q22, to which human TfR2 was mapped.9Tissue distribution of murine TfR2 By RT-PCR, murine TfR2 was detected in all the tissues that we tested, although the expression was low in the heart and kidney (Figure 3A). Relatively high levels of expression were seen in liver and testis when normalized with GAPDH. In the embryo, expression of TfR2 was not detectable until day 11. By Northern blot analysis, expression of TfR2 was the highest in liver and the second highest in spleen (Figure 3B). Expression of TfR2 was not detectable in the intestinal mucosa, where iron absorption takes place. In contrast, expression of TfR1 was ubiquitous, but it was relatively low in the liver. In the embryo, expression of TfR2 increased in the liver during development, whereas expression of TfR1 decreased (Figure 3C-D). In the spleen, expression of TfR1 increased and levels of TfR2 were constant during development (Figure 3C-D).Expression of TfR2 mRNA in MEL cells during erythrocytic differentiation To induce erythrocytic differentiation, we cultured MEL cells with hemin and/or DMSO for 5 days. After 5 days, hemoglobin concentration in the cell lysates increased from 0.03% to 2.46%, 1.21%, or 8.24% in the presence of 2% DMSO, 75 mM hemin, or the combination of 2% DMSO and 75 mM hemin, respectively (Figure 4A, upper panel). The increase in hemoglobin concentration by DMSO was blocked by simultaneous addition of 10 7 M dexamethasone.
Northern blot analysis showed that expression of TfR1 mRNA increased
dramatically and that of TfR2 decreased during either DMSO or DMSO plus
hemin-induced erythrocytic differentiation of these cells (Figure 4A,
lower panel). These changes were blocked by simultaneous addition of
107 M dexamethasone. In contrast, expression of TfR1 mRNA
was not induced and that of TfR2 decreased slightly during erythrocytic differentiation of MEL cells cultured with hemin alone
(Figure 4A).
Expression of murine TfR2 in response to cellular iron status MEL cells were cultured with various concentrations of the iron chelator desferrioxamine (DFO) or ferric nitrate for 2 days, and expression levels of TfR1 and TfR2 mRNA were examined by Northern blot analysis. As shown in Figure 4B, expression of TfR1 was up-regulated by DFO and down-regulated by ferric nitrate. In contrast, expression of TfR2 was largely unchanged by the identical conditions.Transactivation of TfR2 promoter by GATA-1 and C/EBP- also slightly enhanced the activity when using mTfR2-pro-0.3
kb, -0.4 kb, and -2.1 kb (Figure 5). On the other hand, FOG-1, a
cofactor of GATA-1, did not enhance the activity but rather abrogated
the enhancement of the activity by GATA-1. EKLF combined with GATA-1
showed a variable response, inhibiting GATA-1 stimulation with the
longest TfR2 promoter (2.1 kb) and slightly stimulating GATA-1 activity
with the shortest promoter (0.3 kb). The strongest TfR2 promoter
activity (16-fold) occurred with the longest TfR2 promoter (2.1 kb)
when stimulated by GATA-1 and C/EBP- (Figure 5).
We have previously cloned human TfR2 as the second receptor for
transferrin. We identified 2 alternatively spliced forms of human TfR2
transcripts, Our previous studies suggested that molecular properties of human TfR1
and TfR2- However, tissue distribution of these receptors was considerably different. Expression of TfR1 occurs almost ubiquitously, but levels are particularly low in the liver19 (Figure 3B). In contrast, expression of TfR2 occurs almost exclusively in the liver19 (Figure 3B). Expression of TfR1 decreased in the liver during development, from embryonic day 13 to postnatal day 1, whereas levels of TfR2 increased dramatically during the same period (Figure 3C). During murine development, hematopoietic cells, especially erythroid cells, appear first at embryonic day 7 to 8 in the yolk sac, and then move to the liver starting on embryonic day 10. Our RT-PCR results shown in Figure 3A indicate that expression of TfR2 starts between embryonic days 8 and 11, which may reflect the development of the liver, where erythropoiesis occurs.20 Expression of TfR1 is regulated at the levels of transcription and posttranscription by factors such as cellular status of iron, oxygen, proliferation, and differentiation.21-26 Expression profiles of TfR1 and TfR2 in response to cellular iron status were also different. Intracellular iron levels regulate expression of TfR1 mainly at a posttranscriptional level. If iron is scarce, iron-regulatory proteins (IRPs) bind to iron-responsive elements (IREs) of the 3'-untranslated region of TfR1 mRNA and stabilize the transcript. In the presence of excess iron, IRPs are released from IREs of the TfR1 mRNA, resulting in degradation of the transcript. Previous reports have shown that in K562 and other cells, a cell membrane-permeable iron chelator (DFO) up-regulates and an excess of iron down-regulates levels of TfR1 mRNA, consistent with our results from Northern blot analysis shown in Figure 4.10,21,27-31 In contrast, expression of murine TfR2 mRNA was not clearly changed by either DFO or iron overloading in MEL cells (Figure 4), which is similar to the findings of human TfR2 in K562 cells.10 TfR1 has been reported to be up-regulated during erythrocytic differentiation in MEL cells.31-33 This is consistent with our results of DMSO-induced differentiation shown in Figure 4. In the experiments with hemin alone, up-regulation of TfR1 during differentiation was not obvious, probably because iron in the hemin may diminish the up-regulation of TfR1. On the other hand, TfR2 mRNA was down-regulated during erythrocytic differentiation of MEL cells. If our differentiation system reflects gene expression in normal erythropoiesis, our results suggest that TfR2 is a dominantly expressed receptor in early erythroid precursors and TfR1 becomes the dominant receptor during differentiation. Together, tissue distribution and expression profiles of TfR1 and TfR2 were quite different in response to iron and during erythrocytic differentiation. These results call into question whether TfR2 is just a second receptor for Tf and functions similarly to TfR1. Inappropriate iron accumulation in the body causes hemochromatosis, and to date, 3 types of hereditary hemochromatosis have been identified. Type 1 is the most common type that is related to mutations of the HFE gene.2 Type-2 hemochromatosis is the juvenile type, the locus of which was recently determined to be chromosome 1q, but the responsible gene is not yet determined.34 Recently, type-3 hemochromatosis was found in 2 families, who had a nonsense mutation at codon 250 of the human TfR2 gene, with a chromosomal locus at 7q22.12 This observation strongly suggests that defects of TfR2 can cause hemochromatosis, suggesting a relation between TfR2 and iron metabolism, but the main function of TfR2 does not appear to be cellular iron uptake. How then might TfR2 regulate iron metabolism? TfR1 can form a complex with HFE, an atypical MHC class I molecule. TfR1 can also physically associate with other MHC class I and II molecules on the cell surface.35 MHC molecules, some of which are presenting self- and/or nonself antigens, are recognized by T lymphocytes; thus, they are involved in the immune response. The primary structure of the extracellular domain of both human and murine TfR2 is similar to that of TfR1, so TfR2 may also be able to bind to some of the MHC molecules, which may affect immune function or iron metabolism. Although the affinity of TfR2 for HFE is low compared with that of TfR1,36 TfR2 may bind to other MHC molecules. Once T lymphocytes recognize TfR1 or TfR2 together with MHC molecules on the cell surface, these cells may produce cytokines that may change the iron status of the body. TfR2 may regulate iron metabolism through such a mechanism. An association between iron homeostasis and the immune response has been proposed by Salter-Cid et al.37 In both man and mouse, elevated levels of expression of TfR2 were
observed in the liver. C/EBP- In this study, we described molecular cloning of murine TfR2 and its expression profile compared with that of TfR1. Further studies defined the transcription factors required for a robust transcription of TfR2. Accumulating evidence suggests that the physiologic function of TfR2 seems to be different from that of TfR1. Murine knockout models for TfR2 will help to clarify the function of TfR2; it is probably involved in iron metabolism, hepatic function, and erythropoiesis.
We thank Dr T. Murate (Nagoya University, Japan) for providing us
with MEL cells, Drs A. Tsang and S. Orkin for plasmids pXM-GATA1 and
pMT2-FOG, and Dr Xanthopoulos for the C/EBP-
Submitted January 30, 2001; accepted May 18, 2001.
Supported in part by grants from the National Institutes of Health, C. and H. Koeffler Fund, Parker Hughes Trust, and Horn Foundation. H.P.K. holds the Mark Goodson Endowed Chair of Oncology and is a member of the Jonsson Cancer Center.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: H. Phillip Koeffler, Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, 8700 Beverly Blvd, B-208, Los Angeles, CA 90048; e-mail: koeffler{at}cshs.org.
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© 2001 by The American Society of Hematology.
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Top
Abstract
Introduction
,
TfR1; 
,
TfR2). The values of postnatal day 1 for spleen and day 13 embryo for
liver are adjusted to 1.0.
