gene expression

of transferrin

Regulation

MARIO M. ZAKIN Unite d’Expression des Genes Eucaryotcs,

Institut

Pasteur,

ABSTRACT Transferrin (Ti) is the iron-transport protein of vertebrate serum. It is essentially synthesized in the liver, but lower amounts are also produced in other organs, such as testis and brain. A number of studies have

been done to characterize the transcriptional elements implicated in the regulation of Tf gene expression in different organs. The results of these studies support the hypothesis that the Tf gene makes use of different combinations of nuclear proteins in different subsets of cells to achieve tissue-specific expression. It is interesting to point out that this occurs in tissues arising from different embryological transferrin 1992.

gene

origin.-Zakin, expression.

Key Words: Iransferrin DNA regulatoiy elements

expression

M.

M.

FASEB

J.

Serioli

Regulation 6: 3253-3258;

cells

of

hepatocytes

75724, Paris Cedex

15, France

around 9 days of development. However, whole embryos from 6 days after gestation have detectable levels of Tf mRNA (Table 1) (6). It is well established that Tf is synthesized by endoderm cells of the visceral yolk sac (7). Surprisingly, the Tf mRNA levels are several fold higher in the VYS than in the adult liver. Thus, it seems reasonable to assume that the VYS synthesizes the Tf needed for embryonic cell growth before and even after liver differentiation. Because several other serum protein genes are also expressed in the VYS, it is possible that all these VYS gene products are involved in feeding and protecting the growing embryo before the liver takes over these functions. In mouse fetal liver, Tf mRNA was detected as early as 11 days after gestation (8). In the rat, the fetal liver mRNA content increases about 2.2 times between the 17th day of gestation and the first postnatal day, then remains constant during the life of the animal (9). This increase approximately parallels the development of the hepatocyte mass of the liver.

In mouse or rat tissues, Tf mRNA (1l)1 IS AN IRON-BINDING, monomeric glycoprotein that carries ferric iron between the sites of its absorption, storage, and utilization (I). Tf belongs to a family of evolutionarily related proteins including invertebrate and vertebrate serum transferrins, lactotransferrin, and melanotransferrin. Analysis of the amino acid sequences of several members of this family indicates that these proteins are composed of two homologous regions corresponding to the NH2terminal and COOH-terminal moities (2). X-ray crystallographic studies of rabbit serum Tf and human lactotransferrim have shown that the two proteins are folded into two globular domains corresponding to the sequence homology regions (3, 4). These two domains show essentially the same polypeptide chain folding, with one iron-binding site present in each lobe. Analysis of the organization of the human Tf and of the ovotransferrin genes indicates that the segments encoding the two protein domains are composed of a similar number of exons. Moreover, introns interrupt the coding sequence, creating homologous exons of similar size in the 5 and 3’ regions of the genes. These observations strongly indicate that present-day transferrins arose by gene duplication, and it has been proposed that this family of genes evolved by a series of independent gene duplications from a common ancestor, this ancestor itself deriving from a primordial gene by internal duplication (5). Tf is an important factor in cellular processes and seems to play complex physiological roles related to cell function, differentiation, and proliferation. In this review, we will discuss different aspects of the regulation of the expression of

ThANSFERRIN

the gene encoding

this essential

TRANSFERRIN ADULT

EXPRESSION

AND

Tf is essentially mouse

embryo,

protein.

content

in kidney, lung,

spleen, heart, and muscle increases during fetal development, reaching a maximum just before birth; these levels drop rapidly after birth and remain stable at a very low level during adult life (10). A different evolutionary pattern is observed with the Tf mRNA content in whole brain and testis; its amount is very low during the fetal stage and increases after birth, reaching in both cases around one-tenth of the liver concentration, a level that remains constant in the adult (10). In the testis, Tf is synthesized in Sertoli cells, which are the major secretory cells of the testis and constitute the only nongerminal cells of the seminiferous epithelium. Tight junctional complexes formed between adjacent Sertoli cells create the hematotesticular barrier. These cells play a major role in the maintenance and control of spermatogenesis by providing the proper microenvironment for the development of the germinal cells. Testicular Tf is one of the essential components for the maturation of germinal cells. In rats, Tf mRNA is present in Sertoli cells as early as postnatal day 5 (F. Guillou, personal communication), but the protein itself is detectable from the 17th postnatal day, at the beginning of spermatogenesis (11).

In recent

years,

evidence

has accumulated

on the in situ

synthesis

of Tf within the central nervous system (CNS). Tf mRNA was first detected in the chicken (12) and later in the rat (9) and human brain. In the human brain, the messenger is observed as early as 10 wk after gestation (13). In the rat brain, the presence of messenger is localized in oligodendrocytes (14) and in the epithelial cells of the choroid plexus (15). On the contrary, Tf mRNA is not observed in the human choroid plexus (16). Tf messenger is also detected in cultured

IN FETAL

ORGANS synthesized in the fetal and adult liver. In the the liver develops from the gut endoderm at

‘Abbreviations: Tf, transferrin; VYS, visceral yolk sac; CNS, central nervous system; FSH, follicle-stimulating hormone; kb, kiobase pairs, kDa, kilodaltons; C/EBP, CCAAT/enhancer binding protein; HNF-3 or 4, hepatocyte nuclear factor 3 or 4.

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TABLE

1. Transferrin expression in some fetal and adult organs

Transferrin

mRNA

or protein

synthesis

is detected

in:

Whole mouse embryo from 6 days after gestation Endoderm cells of mouse embryo visceral yolk sac - Fetal mouse liver from 11 days after gestation - Fetal rat liver; Tf mRNA increases twice from the 17th day after gestation to the 1st postnatal day, then its content remains constant - Rat testis, in Sertoli cells. Tf is synthesized from the 17th postnatal day - Rat oligodendrocytes from the first day after birth and during adult life - Rat choroid plexus during adult life -

astrocytes, oligodendrocytes, and neurons obtained from the rat (17). Detailed studies correlating the development of various cell types and the appearance of Tf-immunoreactivity were performed in the rat brain. Tf-positive cells are first detected in neurons during the fetal stage, with a peak at 4 days before birth and a low activity up to 8 postnatal days. The protein is detected in oligodendrocytes from the first postnatal day, with a peak 8 days after birth. In the adult brain, Tf-immunoreactivity is observed in oligodendrocytes and in the epithelial cells of the choroid plexus. The analysis of these results suggest that the Tf-immunoreactivity in the CNS appears to be related to cell types undergoing proliferation/differentiation (17). Finally, immunochemical studies showed that in young adult human brains Tf is predominantly confined to oligodendrocytes, whereas in aged brains astrocytes contain most of the protein (18).

REGULATION

OF TRANSFERRIN

EXPRESSION

As indicated in the preceding section, the Tf gene is essentially expressed in the liver and the protein is secreted into the plasma, reaching different organs via the bloodstream. In the chicken, the oviduct also produces transferrin, and both liver and oviduct mRNAs are transcribed from the same gene. Because the regulation of the expression of the Tf gene in liver has been extensively reviewed elsewhere (10, 19), we will briefly summarized the results concerning the hepato-specific expression and present some new data concerning the regulation of Tf synthesis in the testis and brain. As shown by McKnight et al. (20), steroid hormones increase Tf mRNA transcription and protein synthesis in the chicken liver; it is interesting that the same regulation was observed in transgenic mice in which chicken Tf was expressed (21). Nutritional iron deficiency also increases Tf mRNA transcription in the chicken liver (20), and to a lesser extent in the rat liver (22). In contrast with these results, studies performed by others with rat Tf indicate that its expression in liver is constitutive and not subject to regulation by either steroids or body iron status (23). In the latter case, a translational and posttranslational influence of iron on transferrin half-life has been postulated. The same authors found a transient influence of glucagon and its second messenger, cyclic AMP, on 11 expression. However, they believe that this phenomenon has no significant physiological role because the transcriptional inhibition observed is brief compared with the half-life of the Tf mRNA and the Tf protein (10). No explanation is found in the literature about the discrepancy observed between the results obtained by the different groups. However, we think that current experiments performed with transgenic mice may rapidly clarify the situation.

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In the chicken oviduct, although steroid hormones strongly regulate Tf transcription (11), nutritional iron deficiency has no effect on the levels of Tf mRNA (24). In the testis, Sertoli cells synthesize several proteins that are implicated in a variety of cellular functions. As indicated previously, Tf is expressed and secreted into the reproductive tract once the blood-testis barrier is developed, at the beginning of spermatogenesis. In rat Sertoli in vitro cultured cells, FSH, insulin, and retinol stimulate both mRNA synthesis and protein secretion whereas testosterone has no significant effect. Moreover, maximum stimulation occurs when cells are treated with a combination of FSH, insulin, and retinol (25). It is well known that among these effectors, only the FSH action on the function and differentiation of Sertoli cells is mediated by an increase in cAMP. Therefore, hormonal regulation of Tf gene expression in rat testis appears to require the combined effect of cAMP and other signal transduction pathways. However, as noted by the authors, the physiological significance of this hormonal regulation detected in vitro remains to be investigated. The existence of blood-brain barriers in the CNS partially restricts Tf supply to the brain. As indicated, it has been demonstrated that the Tf gene is expressed in some cellular types of the CNS. Analysis of cellular and secreted proteins from astrocytes in cultures showed that around 8% of these proteins is induced or repressed by hydrocortisone (26). Tf mRNA levels in astrocyte cultures also appear to be under hormonal control, as hydrocortisone reduces these levels (27). This suggests that this hormone may also be a physiological regulator in vivo. In primary cultures of epithelial cells of rat choroid plexus, treatments with CAMP analogs decrease the levels of synthesized and secreted Tf in the medium. On the contrary, serotonin increases these levels as well as the Tf mRNA values (28). These results suggest that the production and secretion of the protein in the CNS are regulated by hormones and neurotransmitters.

REGULATORY TRANSFERRIN

ELEMENTS GENE

IMPLICATED

IN THE

EXPRESSION

Transcription tion of the

is one of the central control points in regulaeukaryotic gene expression. Initiation of transcription is mediated by the interaction between cu-acting DNA sequences and trans-acting tissue-specific and ubiquitous transcriptional factors. Cu-acting DNA sequences are present in three major control regions: 1) in sequences around the mRNA initiation site, implicated in the formation of the transcription initiation complex; 2) in the promoter regions, localized 5’ from the cap site, whose function is to stimulate the level of transcription initiation; and 3) in enhancer or supressor regions, which are often found several thousand base pairs away from the promoters in the 5’ or the 3’ genomic regions or in the intron sequences. As indicated previously, the Tf gene is expressed in fetal and adult hepatocytes as well as in other limited subsets of cells. One question that may be addressed concerns the identity of the regulatory transcriptional elements implicated in regulation of Tf gene expression in the adult liver, brain, and testis. Some studies have been performed in order to answer this question and the results obtained are analyzed in this section. Transient and stable expression experiments in hepatoma cells were realized with 5’ and 3’ deleted mutants of the 5’ region of human Tf gene (29). These experiments showed that four distinct functional regions are implicated in the regulation of the transcription of the gene in these cells: 1) a

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tissue-specific promoter located between nucleotides -125 to -45; 2) a distal promoter region from nucleotides -620 to -125, which regulates the proximal promoter activity; 3) a negative acting region (nucleotides -1000 to -620), which down-regulates transcription from the Tf promoter; and 4) an enhancer element located between nucleotides 3600 and -3300. Expression from the mouse Tf gene promoter in transgenic mice has confirmed the presence of liver-specific transcriptional elements between nucleotides -139 and +50 and has suggested the presence of distal elements between -581 and -139 that regulate promoter activity (30). In contrast,

liver NE

-

control

A DRII

PRIP PRI

DRI A

Tf

1CATI +39

-

620

-500

-400

-300

-200

-.-

-1 0

-620-

I

+39 493

0’)

+39 +39

-387

0

______

-125

I -

00

fl

0

193

82--52-+30

c

R -125

-100

I GTAAGGAAGGGGGGTTGGGAGAGGGGCTTGGGC

PRII

-93

*****

PRI

-82

-52

________________________________ I ********* AACCCGGCTGCACAAACACGGGAGGTCGATTGCGCCC

I

150

‘V L) a.’ ‘V 0.’

50-

- Hep3B HepG2

- H515

-620 -493

-387

-323 -125

-100

-93

-82

I

I

1

-52

Figure 1. Regulatory elements in the distal and proximal transfertin gene promoter regions (29). A) Map of the protein binding sites present in the first 620 nucleotides upstream the cap site. B) Nucleotide sequence of the promoter regions FRI and PR!!. C) Transient chloramphenicol acetyltransferase (CAT) expression in hepatoma and HeLa cells transfected with the Tf-CAT plasmids described in panel A.

Figure 2. In vitro transcriptional activity of 5-deleted transferrin gene promoter regions. The - 821-9 construct containing the PR! site is able to direct the transcription of a G-free cassette system in the presence of crude liver nuclear extract (33). Control: transcripts synthesized from the adenovirus 2 major late promoter. transgenes containing human Tf 5 ‘-flanking sequences from -152 to +46 were expressed poorly, whereas the DNA sequence between -152 and -622 bp seems to be important for liver expression of the Tf-reporter gene (31). However, it is interesting to note that in transient expression experiments in hepatoma cells, the -150 to +39 bp DNA sequence of the human Tf promoter acts as a negative region, that downregulates transcription from this promoter (E. Schaeffer, unpublished observations). In vitro binding assays show the existence of five protein binding sites in the first 620 nucleotides of the 5’ region of the gene, upstream from the cap site (32). Two of these sites, named PRI (nucleotides -76 to -51) and PRII (nucleotides -103 to -83) for proximal regions I and II, respectively, are localized in the tissue-specific promoter. Transient expression experiments show that the full activity of the promoter requires the integrity of the two PRI and PRII binding sites (Fig. 1) (29). The activity of the promoter drops to about 15% when the PRI site is mutated and to 30% when the PRII site is mutated (E. Schaeffer, unpublished observations). Using the G-free cassette system in in vitro transcription assays, it was determined that the proteins interacting with PRI are transcriptional activators. Indeed, the PRI site, together with its own TATA box or with a canonical TATA box, is able to direct the transcription of the cassette in the presence of crude liver nuclear extracts (Fig. 2) (33). Thus, transient expression experiments have shown that PRI and PRII are both necessary to obtain high, hepatic-specific expression (Fig. 1). In contrast, in in vitro transcription assays, the nuclear factor interacting with the PR! region is the only protein whose binding is needed to promote liver-specific transcription (Fig. 2). A similar situation exists in the case

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of other liver-specific genes, the c 1-antitrypsin and the albumin genes. It would seem that as the biological complexity of the experimental system is increased (from in vitro to transfected cells in culture, to transgenic animals), the number of regulatory elements needed to obtain maximal expression increases concomitantly (33). Transfection experiments were also carried out using primary cultures of rat Sertoli cells from 17 days of age; that is, at the beginning of spermatogenesis. In this case, the promoter was localized between nucleotides -100 to + 39. In vitro assays show the existence of three protein binding sites in the promoter: PRII, PR!, and a third one situated around the TATA box. The transient expression experiments indicate that the behavior of each analyzed vector in both cells, Hep 3B and Sertoli cells, is different, and the only mutation that substantially modified the promoter activity is the PRII mutation. Finally, a transcription base level is observed when the -52/+39 vector is transfected (34). Thus, the transient expression experiments strongly suggest that each DNA regulatory element (PR! and PRII of the Tf gene promoter) participates differently in the mechanisms governing hepatoma or Sertoli-specific gene expression. What is known about the transcriptional factors interacting with the Tf gene promoter? In the liver system, several factors proof offer that the protein interacting with PRII belongs to the C/EBP family of nuclear factors (35). First, it is a heat-stable protein, and indeed crude liver nuclear extracts heated 5 mm at 80#{176}C still protect the PRII site in DNase I footprinting experiments. Second, pure C/EBPa protects the PR!! site with a pattern similar to the crude liver extract in the same type of assays. Finally, antibodies specifically directed against C/EBPa interact in a gel mobility shift assay, with the main retarded complex obtained between the

PRII

region

and

partially

purified

liver

nuclear

factors

(Fig. 3) (36). To analyze the nuclear factors interacting with PRI, crude liver nuclear extracts were chromatographed on a heparin-Sepharose column and different fractions were obtained after elution of the proteins by using increasing molarities of a KC1 solution. Several proteins are able to interact with the PR! promoter region. Complementation experiments performed between the different eluted fractions of the heparin-Sepharose column modify the binding affinity to PR! for some of the proteins. Some information exists for the proteins eluted at 0.2 M and at 0.5 M KCI. The 0.2 M factor was recently purified, cloned, and sequenced (37). It is a protein that interacts specifically with pyrimidine-rich, single-strand DNA sequences and is capable of unwinding double-stranded DNA in order to interact with its singlestrand target sequence. This factor, named PYBP, is not implicated in the cell type-specific expression of the Tf gene, but may be implicated in the process of transcriptional activation; it is a ubiquitous factor with a molecular mass of 58 kDa. PYBP is almost identical to its human counterpart, PTB (38). Analysis of its primary sequence shows the existence of four internal repeats, each containing the ((3a(3)(I3afl) structure characteristic of the RRM motifs present in RNA or single-strand DNA binding proteins. The protein eluted at 0.5 M KC1 seems to be mainly HNF-4 (39), as antibodies specifically directed against this liver-enriched transcriptional factor interact with the major 0.5 M KC1 fraction-PR! complex (E. Schaeffer and D. Part, unpublished observations). Crude testis nuclear extracts were also chromatographed on a heparin-Sepharose column, and several fractions were eluted at different concentrations of a KCI solution. None of these eluted fractions interact with antibodies directed against C/EBPa or HNF-4 (E. Schaeffer and D. Part, un-

3256

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1992

PROBE

Ii

PRII

U)

a.

123456 Figure 3. Gel shift analysis in the presence of antibodies directed against C/EBPa, using partially purified liver nuclear factors (36). Probes: Ii is an oligonucleotide containing the A domain sequence of the transferrin enhancer. This sequence is the target for a nuclear factor different from C/EBPa. PR!! is an oligonucleotide containing the PRII region of the transferrin gene promoter. pIS: assays performed in the presence of serum from a nonimmunized rabbit. IS: assays performed in the presence of rabbit antiserum directed against C/EBPa. The arrow indicates the band corresponding to the interaction between the PR!! region and C/EBPa in lanes 4 and 5. This band disappears in the presence of antiserum (lane 6).

published observations). With testis extracts, several proteins are able to interact with the PR! region. The protein present in liver nuclear extracts and eluted at 50 mM KC1 interacts with the PRI region of the Tf gene, with the APF1 sequence of the apolipoprotein CIII promoter, and with regulatory regions of the liver-specific genes antithrombin III and aantitrypsin. However, the testis nuclear protein interacts only with the PR! region of the Tf gene. Thus, even if PRI and PR!! Tf protein binding sites are both involved in the hepatocyte and in the Sertoli gene expression, the nuclear factors interacting with these crucial sites for the promoter activity appear to be different in both cell types. As indicated before, an enhancer region was detected 3.6 kb upstream from the TfmRNA initiation site (29). This enhancer is active in hepatoma cells. Transient expression experiments and in vitro DNA protein binding assays indicate that the Tf enhancer is organized into two distinct structural and functional domains, A and B (40). Domain A, when multimerized, is able by itself to stimulate transcription from the 5V40 promoter but not from the Tf promoter. It contains only one protein binding site, and in vitro transcription assays using the G-free cassette system show that the proteins binding to the A domain are transcriptional activators. The DNA sequence target of these proteins, 5’-’JDTT’R]CT-3’, was determined by methylation interference experiments. This sequence was confirmed by directed mutagenesis, and indeed the mutation of the dinucleotide 5’-TG inhibits enhancer activity. Two liver proteins are able

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to bind to the TGT3 sequence, with different affinities. The TABLE 2. Detection of transferrin and liver-enriched transcriptional factors two proteins were purified by affinity chromatography: one in some tissues was eluted at 0.3 M KC1 and the other at 0.6 M KCI (34). Gel mobility shift assays performed in the presence of Choroid plexus Testis Brain Liver specific antibodies indicate that the protein eluted at 0.6 M KC1 is HNF3-a (41), a member of a liver-enriched transcrip+ + + +a TF tional factors family (42). The other protein has a molecular “ Traces HNF-4 mass of 45 kDa and does not interact with antibodies directed + + C/EBPs against HNF-3a, HNF-3/, or HNF-3y (I. Petropoulos, Traces + HNF-3cm unpublished observations). a + indicates the presence of the protein in the corresponding tissue. indicates the absence of the protein in the corresponding tissue. Domain B has no enhancer activity by itself but is able to block the activity of a downstream negative element. In the presence of the Tf promoter, enhancer activity requires the association of the two domains, A and B. Domain B contains antisera directed against the liver-enriched HNF-3 family of four protein binding sites interacting with at least three liver factors. proteins: the NFl factor (43) that interacts with two sites; In conclusion, the promoter and the enhancer activities of AP4 (44) binding to another site; and a third factor, not yet the Tf gene were analyzed in two systems, the hepatic and identified. Directed mutagenesis assays indicate the importhe Sertoli systems. In the hepatic system, the Tf gene may tance of each binding site for full enhancer activity (C. Aug#{233}- use two liver-enriched transcriptional factors, C/EBPa and Gouillou, unpublished observations). In addition, in vitro HNF-4 in the promoter, and in the enhancer, HNF-3a and cross-competition experiments using wild-type and mutated others ubiquitous factors, in a Tf-specific combination. In sequences show that a strong cooperation in binding exists Sertoli cells, where the enhancer is not active, the regulatory between the different transcriptional factors interacting with elements PR! and PR!! participate differently in the mechathe B domain (40). nisms governing cell type-specific expression, and the tranAll these results indicate that the Tf DNA enhancer and scriptional factors interacting with the promoter are different the proteins interacting with it constitute a precise molecular from C/EBPa and HNF-4 (Fig. 4). Table 2 contains data structure specifically maintained through protein-DNA and concerning the presence or absence of Tf and liver-enriched strong protein-protein interactions. This organization of the transcriptional factors in some tissues. From this data it is Tf enhancer may have important functional implications. Inreasonable to postulate that the transcriptional factors used deed, a variation in the amount of a single factor should by the Tf gene for its expression in epithelial cells of mouse result in a strong modification of enhancer activity. This emor rat choroid plexus are different from those used to achieve phasizes the importance of each single factor in the overall liver-specific expression. The results presented in this review support the idea that modulation of the enhancer function. In Sertoli cells, where the amount of Tf mRNA is 10-fold the Tf gene requires different combinations of factors in less than in liver, the enhancer is not active (34). Footprintdifferent subsets of cells to achieve tissue-specific expression, ing experiments show that the four protein binding sites of and it is interesting to note that this occurs in tissues arising the B domain are protected in the presence of crude testis from different embryological origin. Indeed, hepatocytes nuclear extracts; on the other hand, the A domain is either arise from the endoderm; in the testis, Sertoli cells arise from not protected at all or only weakly protected. However, a the mesoderm and nervous cells from the ectoderm. protein is able to interact with the A domain in gel shift moTransfection experiments using astrocyte, oligodendrobility assays; this interaction is specific, as shown by competicyte, and neurone cell cultures, and in vitro protein-DNA binding assays using corresponding protein nuclear extracts, tion experiments in the presence of homologous and heterwill be of great interest in order to detect the regulatory eleologous sequences. This protein is not recognized by any ments implicated in Tf gene expression in the brain. This information will allow comparison between the different DNA Translemn promoteror#{231}anization regions and the nuclear factors responsible for Tf gene transcription in the adult liver, testis, and brain. Full understanding of the cellular mechanisms implicated in the activaC/EBPa HNE4 tion and tissue-specific Tf expression will require isolation of the molecular components involved. This necessitates the purification and cloning of the remaining uncharacterized in hepatocytes ____; factors involved in the Tf gene transcription in different cell -102 -83 -76 -52 types.

in Sertoli cells -102 Figure

4. Transferrin

gene

-83

-76

-52

promoter. In hepatocytes, the liverenriched transcriptional factors CIEBPa and HNF-4 may interact with the PR!! and PR! regions of the transferrin gene promoter, respectively. In Sertoli cells, the transcriptional factors interacting with the promoter are different from C/EBPa and HNF-4.

I am grateful to N. Duchange and F Saul for critical reading of the manuscript and to the members of the Laboratoire d’Expression des Genes Eucaryotes for generously providing unpublished results and for critical discussions that allowed this review to be realized. I also thank E. Croullebois for typing the manuscript. This work was supported by the Centre National de Ia Recherche Scientique (Unite de Recherche Associ#{233}e 1129). REFERENCES 1. Aisen, P., and Listowsky, I. (1980) Iron transport and storage proteins. In Annual Review of Biochemistry (Snell, E. E., Boyer, P. 0., Meister, A., and Richardson, C. C., eds) pp. 357-393, Annual Reviews Inc., Palo Alto, California

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ZAKIN The FASEB Journal 3258 Vol. 6 November 1992 www.fasebj.org by Kaohsiung Medical University Library (163.15.154.53) on November 23, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber

Regulation of transferrin gene expression.

Transferrin (Tf) is the iron-transport protein of vertebrate serum. It is essentially synthesized in the liver, but lower amounts are also produced in...
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