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Food Science and Human Nutrition Department and Center for Nutritional Sciences, University of Florida, Gainesville FL 32611-0370
2To whom correspondence should be addressed. E-mail: rjc{at}gnv.ifas.ufl.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • zinc • zinc transporter • rats • gene expression • zinc metabolism
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. However, the basic mechanism
that is responsible for the physiologic outcome of zinc deficiency or
excess has not been established.
Intracellular homeostasis of zinc is believed to be critical because of
the different biological roles that zinc performs. To attain
homeostasis under different conditions, cells must adjust the rate of
zinc uptake and efflux, binding to intracellular and extracellular
proteins or other molecules, and sequestration into vesicles or
organelles (2)
. This suggests that proteins involved in
controlling such processes would be regulated directly by zinc. In this
way, metallothionein
(MT),3
an extensively studied protein modulated by zinc levels, helps to
regulate the intracellular levels of free zinc through intracellular
binding (3)
. However, much less is known about the
mechanisms of cellular zinc influx and efflux or transport into or out
of vesicles or organelles and their regulation.
Four members of the family of mammalian zinc transporters (ZnT) have
been characterized, i.e., ZnT-1, ZnT-2, ZnT-3 and ZnT-4
(4
5
6
7)
. Hydrophobicity plots suggest that these four
proteins have six transmembrane-spanning domains, with the N and C
termini located intracellularly, based on the positive inside rule
(8)
. They also have a conserved His-rich region
between transmembrane-spanning regions IV and V, which is predicted
to form a cytoplasmic loop and is likely to be responsible for the zinc
binding (5
,9)
. More than six transmembrane domains are
generally necessary to form a pore for translocation of metal ions;
therefore, it is possible that these transporters function as homo- or
heterodimers. Although no direct functional evidence exists to date to
confirm that these proteins are transporters of zinc, there is ample
indirect evidence to correlate zinc transport function to the ZnT
family. The transfection of zinc-sensitive BHK cells with rZnT-1 or
rZnT-2 increased zinc resistance, which, in the case of rZnT-1, was due
to increased efflux (5)
. However, for rZnT-2,
sequestration of zinc in intracellular vesicles appears to be the
reason for the increased resistance (6)
. In addition,
ZnT-4, when expressed in a zinc-sensitive yeast strain, also
conferred zinc resistance to yeast cells (4)
.
A construct with a fluorescent protein fused to the C-terminus of
rat ZnT-1 showed that this protein is located in the plasma membrane of
BHK cells (5)
. It has been reported that ZnT-1, although
expressed in enterocytes, is not expressed in the goblet cells and
lamina propria of small intestine (10)
. Furthermore, they
localized the protein to the basolateral membranes of enterocytes and
renal tubular cells, as well as the villous yolk sac of the 18-d
placenta (11)
. Using a construct with a fluorescent
protein, ZnT-2 was localized to acidic vesicles that accumulate zinc
(6)
. Polymerase chain reaction (PCR) data suggest that
this transporter is expressed only in small intestine, kidney, testis
and seminal vesicles (7)
. ZnT-4 is widely expressed and is
likely to be localized in endosomal vesicles (9)
. A
prematurely terminated form of ZnT-4 is responsible for the lethal milk
(lm) syndrome (4)
. This syndrome is
characterized by the insufficient zinc transfer by the mammary gland to
the milk (12)
, causing zinc deficiency in the pups
(13)
; consequently, ZnT-4 has been implicated in the
transport of zinc into milk by the mammary gland.
The integration of zinc transporter regulation in different organs is an important mechanism for complex organisms to adapt to different zinc intakes and, in this way, maintain a relatively constant zinc supply even during major changes in dietary zinc intake. The aim of this study was to evaluate the coordinate regulation of the zinc transporters ZnT-1, ZnT-2 and ZnT-4 during zinc deficiency and supplementation and an acute dose of oral zinc in specific tissues involved in zinc homeostasis.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Sprague-Dawley rats (Harlan, Indianapolis, IN) with a starting weight
of 175–200 g were housed individually in stainless steel
wire-bottomed cages with a 12-h light:dark cycle. For the zinc
deficiency/supplementation experiments, male rats were given free
access to deionized water and a modified AIN-76a–based pelleted diet
(14)
containing either <1 (deficient), 30 (adequate) or
180 (supplemental) mg Zn/kg diet for 2 wk (15)
. An
additional group consuming the 30 mg Zn/kg diet was pair-fed to the
intake of the <1 mg Zn/kg group to correct for the decrease in the
food intake produced by zinc deficiency. For the oral dosing
experiments, male rats were fed commercial rodent diet (Teklad 8604,
Harlan; 60 mg Zn/kg) and municipal water. One group received saline
containing zinc (as zinc sulfate) to a final dose of 70 mg/kg body by
feeding tube and the other group only saline 2 h before they were
killed and the tissues removed. These rats were deprived of food
12 h before the oral dose but had free access to water. Tissues
for the distribution study were collected from male rats. The placenta
and mammary glands were collected from a timed pregnant rat and
lactating rats, respectively. Those rats were all fed the commercial
rodent diet and municipal water. Zinc concentrations in serum and the
diets were measured by atomic absorption spectrophotometry
(16)
. All procedures were approved by the University of
Florida Institutional Animal Care and Use Committee.
ZnT-1, ZnT-2, ZnT-4, and MT-1 cDNA probes.
ZnT-1 cDNA was of a 737-bp fragment prepared as reported previously
(10)
. An EST clone (RKIBA89) containing part of the ZnT-2
coding sequence (from 849 to 1443) in the pT7T3D-Pac vector was
purchased from ATCC (Rockville, MD). This clone was digested with Bbr
PI and Not I restriction enzymes to remove the poly A tail, religated,
transfected into Epicurian Coli Ultracompetent Cells (Stratagene, La
Jolla, CA) and selected on LB-ampicillin plates. The plasmid was
isolated using QIAprep plasmid preparation reagents (Qiagen, Valencia,
CA) and sequenced to confirm its identity. To generate the ZnT-4 cDNA
probe, total RNA was isolated from mouse (C57BL/6 strain) brain,
treated with RNase-free DNase I (Gibco BRL, Bethesda, MD) and
reverse transcribed using an anchored oligo dT primer
(CAA)T12 and Superscript II reverse transcriptase (Gibco
BRL). PCR primers for ZnT-4 were synthesized from sequences "cDNA
2–18" and "cDNA 2–24" to produce a 1051-bp cDNA fragment
(4)
. Amplification was performed in a
25-µL volume containing 1.4 µmol/L of
each primer, 0.2 mmol/L of each dNTP, 1.5 mmol/L
MgCl2, 5 mmol/L KCl, 10 mmol/L Tris (pH 8.3) and 1
U Taq DNA Polymerase (Roche, Indianapolis, IN), and thermal
cycled through seven cycles of 94°C/45 s, 56°C/50 s, 72°C/2.5 min
followed by 30 cycles of 94°C/45 s, 58°C/50 s, 72°C/2.5 min. The
PCR product was ligated into pPCR-Script vector (Stratagene) and
transfected into Epicurian cells as above. Plasmid containing the PCR
product was isolated as above and sequenced. All cDNA probes were
radiolabeled with 
-32P dCTP using Ready-To-Go DNA
Labeling Beads (Amersham Pharmacia Biotech, Piscataway, NJ).
RNA extraction and Northern analysis.
The rats were anesthetized with methoxyfluorane and killed by
exsanguination. Tissues were quickly excised and total RNA was
isolated. Briefly, a section of intestine (20 cm; starting 1 cm caudal
to the pyloric sphincter) was excised, and the mucosa was removed after
flushing the intestine with cold 9 g/L NaCl. In some experiments,
villous and crypt cells from this section of intestine were separated
(17)
before RNA extraction. Cell type fractionation was
verified by light microscopy and alkaline phosphatase activity. A lobe
of liver (
500 mg) and one kidney were also collected. Tissues were
immediately homogenized in 4 mL of Tripure (Roche); total RNA was
extracted according to the manufacturer’s protocol and stored in
diethyl pyrocarbonate–treated water.
For quantitative Northern analysis, equal amounts of total RNA (15
µg) were denatured in formaldehyde and formamide, and
electrophoresed through 1% agarose gels containing 2.2 mol/L
formaldehyde and 2-(N-morpholino)propanesulfonic acid
buffer (10)
. The RNA was transferred to GeneScreen
membranes (Du Pont/NEN, Boston, MA) by capillary transfer and
hybridized with the probes at 2 x 109 cpm/L according
to the GeneScreen protocol. After exposure to X-ray film for image
detection, the membranes were stripped in a boiling solution of 1%
SDS, 1 mmol/L EDTA, 10 mmol/L NaH2PO4 and 148
mmol/L NaCl, and hybridized with either a ß-actin or 18S rRNA probe
to normalize for RNA loading (18)
. Exposure to X-ray
film varied from 4 d to 2 wk. Image intensity of the
autoradiographs was determined by scanning densitometry
(10)
. Alternatively, Northern blots from the tissue
distribution experiments were exposed to storage phosphor screens for
detection and analysis on a Storm 840 Phosphorimager (Amersham
Pharmacia Biotech/Molecular Dynamics, Sunnyvale, CA). Exposure to the
phosphor screens was usually 1 wk for ZnT-2 cDNA and 2–3 d for ZnT-1
and ZnT-4 cDNAs.
Statistical analysis.
One-way ANOVA, followed by Student-Newman-Keuls multiple comparison test, was used to analyze data from the diet experiments, whereas data from the oral dose experiments were analyzed with two-tailed Student’s t test. The level of significance was set at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Serum zinc concentrations were significantly influenced by the low zinc
intake but not by the supplemental intake level (Table 1
). The oral zinc load produced a significant change in serum zinc
concentrations. As shown in Figure 1
, mRNA levels of kidney MT, a gene responsive to zinc intake, responded
to changes in zinc in both dietary and oral dose experiments.
Corresponding expression of ß-actin is also shown. These results
demonstrate that the treatments used affected zinc status.
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Of the three transporter genes examined in this report, ZnT-1 and ZnT-4
were found to be distributed ubiquitously. Nevertheless, their
abundance varied greatly among tissues (Fig. 2
). The highest expression of ZnT-1 was in the placenta, kidney and small
intestine, followed by adipose tissue, liver, spleen and thymus. In
contrast, ZnT-2 expression was highest in small intestine and kidney,
with lesser amounts in placenta, but no appreciable ZnT-2 mRNA in
stomach, liver, spleen, thymus and adipose tissue (Fig. 2)
.
Distribution of ZnT-4 mRNA, although seen in all tissues tested, was
most highly expressed in the small intestine and mammary gland.
However, ZnT-4 mRNA in the latter decreased with the length of
lactation. In addition, intestinal expression of all three zinc
transporters was greater in the villous cells of the small intestine
than in cells of the crypts. This localization may be a reflection of
their potential function related to zinc acquisition or excretion. As
reported previously (10)
, two transcripts that appear to
have a constant ratio have been observed for ZnT-1. ZnT-2 mRNA also
showed evidence of two transcript sizes, which appeared to have a
constant ratio of abundance. ZnT-4 mRNA seemed to be processed to a
single transcript. The major bands of ZnT-1 mRNA and ZnT-4 mRNA were
the largest, migrating just behind the 28S RNA. ZnT-2 was the smallest
of the three mRNAs, with the major band migrating just below the 28S
RNA (data not shown). Because of the differences in probe specificities
due to their lengths (594–1050 bases), the data obtained by
phosphorimaging were not used to make direct comparisons of the
relative abundance of the three ZnT mRNAs.
|
Quantitative Northern analyses of each of the ZnT mRNAs were derived
from individual rats in each dietary group and were normalized to
ß-actin. As shown in Figures 3
-5, relative expression of these ZnT genes was markedly different in
small intestine, liver and kidney. In the small intestine, ZnT-1 mRNA
levels (Fig. 3)
were significantly greater in the supplemented rats.
ZnT-1 mRNA expression seemed to be refractory to the 1 mg/kg (zinc
deficient) intake level and was comparable to the relative abundance
observed with 5 mg/kg intake used previously (10)
. In
contrast, intestinal ZnT-2 mRNA levels very closely reflected zinc
intake (Fig. 3)
. It is of particular interest that ZnT-2 expression was
not detectable when the rats were fed the zinc-deficient diet. This
differential response suggests that this zinc transporter gene is
closely regulated by the zinc supply. It is also of interest that in
small intestine, ZnT-2 expression was correlated (r = 0.93) with metallothionein expression. Intestinal ZnT-4 mRNA levels
were significantly reduced by the zinc-deficient diet, but the
decrease was far less than that observed for ZnT-2. However, this
difference may be related to decreased food intake rather than the
dietary zinc levels, given the levels observed in the pair-fed
group.
|
). There was a trend toward reduced ZnT-1 mRNA when the deficient diet
was fed (P = 0.14), but the difference was not
significant with the number of rats used in this study. A similar trend
with ZnT-4 mRNA was not observed because it appeared to be equivalent
in all four dietary groups. Under these dietary conditions, ZnT-2 mRNA
was not detected in the liver.
|
). ZnT-1 expression in the zinc-deficient rats was 50% that
found in the two groups fed adequate amounts of zinc. Zinc
supplementation increased ZnT-1 mRNA levels by 65% compared with
the zinc-adequate groups. Similarly, ZnT-2 mRNA responded markedly
to dietary zinc intake, and the response was comparable to that
observed in the small intestine. Zinc deficiency reduced expression to
20% of that found in the zinc-adequate rats, whereas zinc
supplementation yielded an 80% increase compared with the adequate
groups. In contrast, kidney ZnT-4 expression was not influenced by zinc
intake under these dietary conditions.
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It is likely that transporter expression, as presented in the section
above, represents a steady state that reflects the outcome of
regulation brought about when animals have adapted to a specific level
of zinc intake. An alternative approach is to examine how animals
regulate zinc transporter expression immediately after short-term
acute increases in zinc intake. A 2-h interval after an oral zinc load
(70 mg Zn/kg body) was sufficient to markedly increase the amount of
zinc available to tissues (Table 1)
as indicated by elevated serum zinc
levels. As a basis for comparison of the induction of ZnT expression
after the zinc load, the increase in kidney MT mRNA is shown (Fig. 1)
.
This represents a 1200% increase, which exceeds the zinc-induced
changes in expression of any ZnT.
In small intestine, ZnT-1 and ZnT-2 mRNAs increased 600 and 370%
(Fig. 6
), respectively, after the zinc load. The response in ZnT-1 expression
closely followed that reported earlier (10)
. Under these
conditions, oral zinc actually decreased ZnT-4 mRNA levels, but not
significantly (P = 0.11) (Fig. 6)
. Of major
interest is that the oral zinc load induced ZnT-2 expression in liver
by 700% (Fig. 7
). This finding is in contrast to data from the tissue survey presented
here in Figure 2
and those from another laboratory (7)
,
suggesting that under normal conditions, ZnT-2 is not expressed in
liver. Liver ZnT-1 mRNA levels were elevated 300%, but ZnT-4 mRNA
levels were not changed in response to the oral zinc load. As shown in
Figure 8
, both ZnT-1 and ZnT-2 mRNAs were elevated (700 and 330%, respectively)
in kidney. As in other tissues, ZnT-4 expression in kidney was
refractory to the acute increase in zinc intake. It is relevant to
point out that overnight food deprivation may have produced some change
in ZnT expression in tissues from these rats relative to those in the
diet studies (data not shown). This suggests that some ZnT genes may be
responsive to hormones that have regulatory roles in zinc metabolism.
For example, under basal conditions, no ZnT-2 mRNA was detectable in
the liver, but rats that were food deprived and dosed orally with
saline showed some level of expression (Fig. 7
B), suggesting
that hormones associated with a response to food deprivation and/or
stress have a regulatory influence on this transporter.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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5
6)
. Direct functional
evidence, as has been performed on the iron transporter (DMT-1), which
uses a proton coupled mechanism (19)
, has yet to be
carried out on the ZnT family members. Nevertheless, indirect
physiologic evidence and sequence analysis with other transporters
provide powerful evidence that these membrane-spanning proteins are
cation transporters.
The tissue distribution of these ZnT mRNAs is consistent with different
magnitudes of influence on zinc metabolism. ZnT-1 has been the most
widely characterized. Originally generated in mutagenized baby hamster
kidney cells and localized to the plasma membrane, the resistance to
zinc upon ZnT-1 overexpression suggested an export function
(5)
. Subsequently, we localized native ZnT-1 to the
basolateral membrane of enterocytes and distal renal tubules
(10
,11)
. Our present results have shown that ZnT-1
expression is markedly regulated in kidney by the dietary zinc supply.
Increased expression in the kidney during excess zinc intake would
initially suggest a role in zinc excretion. However, because urinary
zinc excretion is normally low (20)
, zinc reabsorption may
be a function for this transporter. Immunofluorescence localization of
ZnT-1 in kidney (11)
supports a function in reabsorption.
Of potential relevance is the abundance of ZnT-1 in adipose tissue.
Zinc has been suggested to have a role in carbohydrate/lipid metabolism
(21)
, and this relatively high ZnT-1 expression may
suggest that adipocytes carefully regulate intracellular zinc levels.
It is also of interest that placental ZnT-1 expression is comparable to
that observed in intestine and kidney, indicating a possible role in
maternal zinc transfer. This is in agreement with immunofluorescence
localization of ZnT-1 to the villous yolk sac of the 18-d rat placenta
(11)
. The relative abundance of ZnT-1 mRNA compared with
those for ZnT-2 and ZnT-4 also suggests a primary role for ZnT-1 in
maternal to fetal zinc transport in rats.
The responsiveness of ZnT-2 to zinc is greater than that of ZnT-1.
Furthermore, ZnT-2 is limited in expression to major organs of zinc
metabolism, i.e., intestine, kidney and placenta. These observations
agree well with the proposal that, through zinc sequestration into
endosomal vesicles during ZnT-2 overexpression in transfected cells,
this transporter protects cells from damage related to toxic levels of
zinc (6)
. This metabolic flexibility may be important in
controlling or buffering transcellular zinc movement within enterocytes
and/or zinc reabsorption by the kidney during a constantly varying zinc
intake, which is common to most species. Our results suggest that,
during a high zinc intake, ZnT-2 may have a similar function in the
liver and thus influence hepatic zinc release. Specifically, if ZnT-2
is shown to be vesicular in hepatocytes, an efflux role for this
transporter would lead to vesicular sequestration and more limited
distribution of zinc to other tissues and/or excretion via the biliary
route.
As mentioned above, there is a high correlation between the expression
of ZnT-2 and MT in response to zinc. More than likely, the ZnT-2
promoter will be found to have multiple metal response elements, as
does the MT promoter (22)
. Proof of such a mode of
regulation will require developing ZnT-2 promoter-reporter gene
constructs, their transfection into appropriate cells in culture and
analysis of reporter gene expression in response to zinc added to or
removed from these cell cultures.
A ubiquitous distribution of ZnT-4 (9)
, originally cloned
as a developmentally regulated cDNA (Dri 27) (23)
, may
have a vesicular localization in transfected cells. Our results show
that, in liver, kidney and small intestine, changes in zinc status do
not influence ZnT-4 mRNA levels. This is consistent with a report which
found that zinc deprivation did not influence ZnT-4 expression in small
intestine, testes or brain (9)
. We also report here that
expression is highest in the mammary gland and villous cells of the
small intestine, and furthermore note that expression in mammary gland
decreases by d 22 of lactation. This follows the reduction in zinc
concentration of milk found with length of lactation (24)
,
an occurrence that is not changed by zinc supplementation
(25
,26)
. The murine homologue of ZnT-4 was cloned during
mapping of murine chromosome 2 to examine genes responsible for
metal-related otolith defects (4)
. They demonstrated
high expression of ZnT-4 mRNA in mouse mammary cell lines and provided
a link to a mutation that causes lm syndrome. The
lm mutation results in diminished zinc transport into milk
(12)
, leading to a fatal zinc deficiency in the nursing
pups (13)
.
In summary, these data provide the first comparative view of zinc transporter gene regulation in an animal model. The results show that ZnT-1, ZnT-2 and ZnT-4 have unique patterns of distribution, and their regulation reflects a spectrum of sensitivity to zinc. The data also imply that some transporters are expressed constitutively, whereas others are highly regulated in tissues responsible for zinc homeostasis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: lm, lethal
milk; MT, metallothionein; PCR, polymerase chain reaction; ZnT-1, zinc
transporter-1; ZnT-2, zinc transporter-2; ZnT-4, zinc transporter-4.
Manuscript received August 29, 2000. Initial review completed September 20, 2000. Revision accepted October 7, 2000.
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 M. J. Chung, C. Hogstrand, and S.-J. Lee Cytotoxicity of nitric oxide is alleviated by zinc-mediated expression of antioxidant genes. Experimental Biology and Medicine, October 1, 2006; 231(9): 1555 - 1563. [Abstract] [Full Text] [PDF]
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R. J. Cousins, J. P. Liuzzi, and L. A. Lichten Mammalian Zinc Transport, Trafficking, and Signals J. Biol. Chem., August 25, 2006; 281(34): 24085 - 24089. [Full Text] [PDF]
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 T. B. Aydemir, R. K. Blanchard, and R. J. Cousins Zinc supplementation of young men alters metallothionein, zinc transporter, and cytokine gene expression in leukocyte populations PNAS, February 7, 2006; 103(6): 1699 - 1704. [Abstract] [Full Text] [PDF]
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 L. E. King, J. W. Frentzel, J. J. Mann, and P. J. Fraker Chronic Zinc Deficiency in Mice Disrupted T Cell Lymphopoiesis and Erythropoiesis While B Cell Lymphopoiesis and Myelopoiesis Were Maintained J. Am. Coll. Nutr., December 1, 2005; 24(6): 494 - 502. [Abstract] [Full Text] [PDF]
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 J. Dufner-Beattie, Z. L. Huang, J. Geiser, W. Xu, and G. K. Andrews Generation and Characterization of Mice Lacking the Zinc Uptake Transporter ZIP3 Mol. Cell. Biol., July 1, 2005; 25(13): 5607 - 5615. [Abstract] [Full Text] [PDF]
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 W. Chowanadisai, S. L. Kelleher, and B. Lonnerdal Zinc Deficiency Is Associated with Increased Brain Zinc Import and LIV-1 Expression and Decreased ZnT-1 Expression in Neonatal Rats J. Nutr., May 1, 2005; 135(5): 1002 - 1007. [Abstract] [Full Text] [PDF]
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 R A Cragg, S R Phillips, J M Piper, J S Varma, F C Campbell, J C Mathers, and D Ford Homeostatic regulation of zinc transporters in the human small intestine by dietary zinc supplementation Gut, April 1, 2005; 54(4): 469 - 478. [Abstract] [Full Text] [PDF]
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 F. Chimienti, S. Devergnas, A. Favier, and M. Seve Identification and Cloning of a {beta}-Cell-Specific Zinc Transporter, ZnT-8, Localized Into Insulin Secretory Granules Diabetes, September 1, 2004; 53(9): 2330 - 2337. [Abstract] [Full Text] [PDF]
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K. B. Andree, J. Kim, C. P. Kirschke, J. P. Gregg, H. Paik, H. Joung, L. Woodhouse, J. C. King, and L. Huang Investigation of Lymphocyte Gene Expression for Use as Biomarkers for Zinc Status in Humans J. Nutr., July 1, 2004; 134(7): 1716 - 1723. [Abstract] [Full Text]
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J. Dufner-Beattie, S. J. Langmade, F. Wang, D. Eide, and G. K. Andrews Structure, Function, and Regulation of a Subfamily of Mouse Zinc Transporter Genes J. Biol. Chem., December 12, 2003; 278(50): 50142 - 50150. [Abstract] [Full Text] [PDF]
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S. L Kelleher and B. Lonnerdal Zn Transporter Levels and Localization Change Throughout Lactation in Rat Mammary Gland and Are Regulated by Zn in Mammary Cells J. Nutr., November 1, 2003; 133(11): 3378 - 3385. [Abstract] [Full Text] [PDF]
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J. Dufner-Beattie, F. Wang, Y.-M. Kuo, J. Gitschier, D. Eide, and G. K. Andrews The Acrodermatitis Enteropathica Gene ZIP4 Encodes a Tissue-specific, Zinc-regulated Zinc Transporter in Mice J. Biol. Chem., August 29, 2003; 278(35): 33474 - 33481. [Abstract] [Full Text] [PDF]
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R. Lee, W. Woo, B. Wu, A. Kummer, H. Duminy, and Z. Xu Zinc Accumulation in N-Methyl-N-Nitrosourea-Induced Rat Mammary Tumors Is Accompanied by an Altered Expression of ZnT-1 and Metallothionein Experimental Biology and Medicine, June 1, 2003; 228(6): 689 - 696. [Abstract] [Full Text] [PDF]
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R. J. Cousins, R. K. Blanchard, J. B. Moore, L. Cui, C. L. Green, J. P. Liuzzi, J. Cao, and J. A. Bobo Regulation of Zinc Metabolism and Genomic Outcomes J. Nutr., May 1, 2003; 133(5): 1521S - 1526. [Abstract] [Full Text] [PDF]
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J. P. Liuzzi, J. A. Bobo, L. Cui, R. J. McMahon, and R. J. Cousins Zinc Transporters 1, 2 and 4 Are Differentially Expressed and Localized in Rats during Pregnancy and Lactation J. Nutr., February 1, 2003; 133(2): 342 - 351. [Abstract] [Full Text] [PDF]
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C. P. Kirschke and L. Huang ZnT7, a Novel Mammalian Zinc Transporter, Accumulates Zinc in the Golgi Apparatus J. Biol. Chem., January 31, 2003; 278(6): 4096 - 4102. [Abstract] [Full Text] [PDF]
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 G. Ranaldi, G. Perozzi, A. Truong-Tran, P. Zalewski, and C. Murgia Intracellular distribution of labile Zn(II) and zinc transporter expression in kidney and MDCK cells Am J Physiol Renal Physiol, December 1, 2002; 283(6): F1365 - F1375. [Abstract] [Full Text] [PDF]
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S. L. Kelleher and B. Lonnerdal Zinc Transporters in the Rat Mammary Gland Respond to Marginal Zinc and Vitamin A Intakes during Lactation J. Nutr., November 1, 2002; 132(11): 3280 - 3285. [Ab |
