1 Department of Nutrition, School of Medicine, University of Tokushima, Tokushima 770-8503, Japan; 2 Department of Internal Medicine, Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri 63110; and 3 Therapeutic Application Development Group, Otsuka Pharmaceutical Company, Tokyo 101-8535, Japan
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ABSTRACT |
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We previously
showed that vitamin A upregulated the expression of bone-type alkaline
phosphatase (ALP) in fetal rat small intestine and rat intestinal IEC-6
cells. In this study, we examined interactions between retinoic
acid (RA) and several growth factors/cytokines on the isozyme
expression in IEC-6 cells. Epidermal growth factor and interleukins
(ILs)-2, -4, -5, and -6 completely blocked the RA-mediated increase in
ALP activity. In contrast, IL-1 markedly increased the activity,
protein, and mRNA of the bone-type ALP only when RA was present.
IL-1
and/or RA did not change the type 1 IL-1 receptor transcript
level, whereas IL-1
enhanced the RA-induced expressions of retinoic
acid receptor-
(RAR-
) and retinoid X receptor-
(RXR-
) mRNAs
and RA-mediated RXR response element binding. The synergism of IL-1
and RA on ALP activity was completely blocked by protein kinase C (PKC)
inhibitors. Our results suggest that IL-1
may modify the ALP isozyme
expression in small intestinal epithelial cells by stimulating
PKC-dependent, RAR-
- and/or RXR-
-mediated signaling pathways.
retinoic acid receptors; retinoid X receptors; protein kinase C; fetal rat small intestine; alkaline phosphatase isozymes
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INTRODUCTION |
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DURING GESTATION,
rat small intestinal epithelial cells drastically change the expression
of alkaline phosphatase (ALP) isozymes (12).
Liver/bone/kidney (LBK) ALP is transiently expressed in the cells
lining the gut and in crypt cells during the first and second
gestational phases. Intestinal ALP first appears during the third
phase, and the level continues to increase. At the same time, LBK ALP
expression rapidly and reciprocally decreases. At present, the
physiological meaning of LBK ALP expression during the early
gestational period is unknown; however, mice lacking the LBK ALP gene
were reported to show abnormal intestinal motility, suggesting that the
transient expression of LBK ALP and rapid changes in the pattern of ALP
isozyme expression during the early gestational phases are essential
events processing normal development of the small intestine
(19). Therefore, it is important to reveal the molecular
mechanisms for regulation of each ALP isozyme expression in fetal small
intestinal epithelial cells. Recently, we showed that retinoic acid
(RA) specifically upregulated the bone-type ALP in rat small intestinal
crypt cells (IEC-6 cells), and we also found that LBK ALP expressed in
the fetal rat intestine was the bone type and that its expression was
markedly upregulated by administration of retinyl acetate to dams
(20). Furthermore, retinoic acid receptor- (RAR-
)
mRNA is expressed in IEC-6 cells and in the fetal rat small intestine
but not in adult tissue (22). Thus IEC-6 cells display
features characteristic of fetal rat small intestinal epithelial cells.
In this study, we further examined the regulation of bone-type ALP
expression in IEC-6 cells. The bone-type ALP-inducing action of RA
shown in IEC-6 cells was not enough to account for the marked expression of the isozyme observed in dams treated with an excess amount of retinyl acetate (20), leading us to consider
that RA-mediated induction of bone-type ALP may be greatly modulated by
additional factor(s). In other words, an exogenous morphogen of RA may
act as a cofactor for distinct endogenous factor(s) in regulation of
bone-type ALP expression in the fetal tissue. On the basis of this
idea, we investigated the effects of several growth factors and
cytokines on ALP expression in IEC-6 cells. RA alone could increase the
ALP expression about threefold. Macrophage colony-stimulating factor
(M-CSF), transforming growth factor- (TGF-
), and tumor necrosis
factor-
(TNF-
) had no effect on the action of RA, but the
induction was completely canceled in the presence of epidermal growth
factor (EGF) and interleukins (ILs)-2, -4, -5, and -6. Furthermore, we
found a unique and specific interaction between RA and IL-1
on
bone-type ALP expression; IL-1
itself had no stimulatory action on
the isozyme induction, but in the presence of RA, it markedly induced
the ALP activity >15-fold. To elucidate the regulatory mechanism for
bone-type ALP expression in fetal small intestinal epithelial cells, in this study we focused on the synergistic effects between RA and IL-1
on the transcriptional activation of the bone-type ALP gene in IEC-6 cells.
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MATERIALS AND METHODS |
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Reagents.
FCS and DMEM were obtained from Flow Laboratories (McLean, VA). RA,
1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), and N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H-8)
were purchased from Sigma (St. Louis, MO). Human recombinant TNF-, IL-1
and -
, IL-2, IL-4, IL-5, IL-6, and M-CSF were provided by
Otsuka Pharmaceuticals (Tokushima, Japan). EGF from mouse submaxillary glands (receptor grade) was purchased from Collaborative Research (Bedford, MA). Human recombinant TGF-
was purchased from King Brewery (Tokyo, Japan). Dibutyryl cAMP (dbcAMP) and bisindolylmaleimide GF-109203X were from Boehringer Pharmaceuticals (Mannheim, Germany). An
enhanced chemiluminescence Western blotting detection system, poly(dI-dC) · poly(dI-dC), [
-32P]ATP
(>2.2 × 1014 Bq/mmol), and T4 polynucleotide kinase
were purchased from Amersham (Little Chalfont, UK).
[
-32P]dCTP (>1.1 × 1014 Bq/mmol)
was obtained from ICN Pharmaceuticals (Costa Mesa, CA). Antisera and
cDNAs for rat LBK ALP and rat intestinal ALP were prepared as described
previously (24). cDNAs for mouse retinoic acid receptor
(RAR)-
, -
, and -
(30) and mouse retinoid X receptor (RXR)-
, -
, and -
(4) were kindly
provided by Dr. P. Chambon, Centre National de la Recherche
Scientifique, Strasbourg, France. IEC-6 cells, mouse F9 teratocarcinoma
cells, and a cDNA for human glyceraldehyde-3-phosphate dehydrogenase
(GAPDH, ATCC 57091) were purchased from the American Type Culture
Collection (Rockville, MD).
Cell culture and analysis of ALP activity in IEC-6 cells.
IEC-6 cells and F9 cells were cultured and maintained as described
previously (20). When IEC-6 cells were grown to 80% of confluence, the medium was changed to DMEM containing 0.1% FCS and
cells were cultured overnight. These cells were treated with one of the
growth factors or cytokines at the indicated concentrations in the
absence or presence of 1 µM RA. After culturing for the indicated
days, IEC-6 cells were washed three times with ice-cold PBS, scraped
with a rubber policeman, and collected in a microtube. The collected
cells were stored in PBS at 80°C until analysis. The stored cells
were disrupted on ice by sonication for 10 s before measurement of
enzyme activities. ALP activity in the whole cell extracts was measured
using p-nitrophenyl phosphate as a substrate according to
the method of Hausamen et al. (6). Protein concentration
was measured according to the method of Lowry et al. (16)
with BSA as a standard.
Immunoblot analysis for LBK ALP. The whole cell extracts from IEC-6 cells and tissue proteins from fetal rat small intestines were subjected to SDS-8% PAGE (40 µg protein/lane) and transferred to a polyvinylidene difluoride membrane. The membrane was blocked with 5% BSA and then incubated for 1 h at 25°C in PBS with a 1:1,000 dilution of rabbit antiserum against rat LBK or intestinal ALP. Bound antibodies were detected using the enhanced chemiluminescence system.
Northern blot analysis.
Total RNA was isolated from IEC-6 cells with an acid guanidinium
thiocyanate-phenol-chloroform mixture (Nippon Gene, Tokyo, Japan).
Total RNA (20 µg) was separated in a 1% agarose gel, blotted, and
ultraviolet crosslinked to a Hybond N+ nylon membrane
(Amersham). Prehybridization of membranes was carried out for 4 h
at 42°C in buffer containing 50% formamide, 6× SSC (1× SSC
consists of 0.15 M NaCl and 15 mM sodium citrate), 1% SDS, 5×
Denhardt's solution (1× Denhardt's solution consists of 0.02%
Ficoll, 0.02% BSA, and 0.02% polyvinylpyrrolidone), and 50 µg/ml
heat-denatured, sheared salmon sperm DNA. Hybridization was performed
overnight at 48°C in a mixture containing 4 vols of prehybridization
solution, 1 vol of 50% dextran sulfate, and 1-5 × 106 cpm/ml of the appropriate cDNA probe. The isolated cDNA
fragments were labeled with [-32P]dCTP by a random
primer kit (Amersham). Membranes were washed and exposed to Kodak X-ray
films at
80°C for the appropriate times, and then films were
developed. Autoradiograph signals were quantified by densitometric
analysis. Each mRNA level was standardized to that of GAPDH mRNA.
RT-PCR.
The rat LBK ALP gene contains two leader exons (exon 1 and exon 2)
giving rise to two alternatively spliced mRNAs in the 5'-untranslated region (28). The rat exon 1 and exon 2 are transcribed
into the bone-type and liver-type transcripts, respectively. For
amplification of the isozyme transcripts, the upstream sense
oligonucleotide specific for exon 1 (5'-AGAGTAGGCTCCCGCCACG-3') or exon
2 (5'-ATCGTGCTGACCTTGCCACA-3') was used, respectively, and the
downstream antisense oligonucleotide was obtained in exon 3 (5'-CAGTGTCAGCCGTTAATTGAC-3') of rat LBK ALP gene. Oligonucleotides
specific for the rat type 1 IL-1 receptor cDNA
(5'-TTGACATAGTGCTTTGGTACAGGGAC-3' and 5'-GAACCTGGTCTTTGCAGACTGTGG-3') and for the rat -actin cDNA (5'-GCGCTCGTCGTCGACAACGG-3' and
5'-GATGGCTACGTACATGGCTG-3') were used for their mRNA amplifications,
respectively (21, 27).
Gel mobility shift assay.
Preparation of whole cell extracts and gel mobility shift assay were
performed as described previously (7). Briefly, IEC-6 cells treated with RA and/or IL-1 were suspended in lysis buffer consisting of 20 mM HEPES, pH 7.9, 25% glycerol, 0.42 M NaCl, 1.5 mM
MgCl2, 0.2 mM EDTA, 0.5 mM phenylmethylsulfonyl fluoride, 0.5 mM leupeptin, 5 mM
trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane, 0.3 mM aprotinin, 1 mM pepstatin, and 0.5 mM dithiothreitol. Whole cell
extracts obtained by ultracentrifugation at 100,000 g for 5 min at 4°C were dialyzed against binding reaction buffer consisting of 10 mM Tris · HCl (pH 7.8), 50 mM NaCl, 1 mM EDTA, 8%
glycerol, 1 mM dithiothreitol, 5 mM MgCl2, and 0.5 mg/ml
BSA. A synthetic double-stranded oligonucleotide
(5'-AGCTAGGTCAGAGCCCAGCT-3'), similar to the putative retinoid X
receptor response element (RXRE) located in the promoter of LBK ALP
exon 2 gene (28), was used to detect RXRE binding
activities. The synthetic nucleotide
(5'-AGCTAGTGCAGAGTTCAGCT-3') was used as a mutant
RXRE competitor. Whole cell extracts (10 µg protein) were mixed with
0.1 ng of the 32P-labeled RXRE oligonucleotide and 1 µg
of poly(dI-dC) · poly(dI-dC) for 30 min at 25°C. The
RXRE-containing complexes were separated in 5% nondenaturing
polyacrylamide gels at 180 V for 2 h at 4°C.
Statistical analysis. All data are expressed as means ± SD for three to eight individual samples per group and were analyzed by one-way analysis of variance using SPSS (release 6.1, SPSS Japan, Tokyo). Differences between means were tested by Scheffé's test. A P value of <0.01 was considered to be statistically significant.
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RESULTS |
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Stimulatory effect of IL-1 on RA-mediated increase of ALP activity
in IEC-6 cells.
Treatment of IEC-6 cells with 1 µM RA for 5 days increased ALP
activity about threefold (Fig.
1A). When growth factors (EGF, M-CSF, TGF-) and cytokines (TNF-
, ILs-1, -2, -4, -5, and -6) at
the indicated concentrations were added simultaneously with 1 µM RA
to IEC-6 cells, M-CSF, TGF-
, and TNF-
did not affect the
RA-mediated increase in ALP activity, whereas EGF, IL-2, IL-4, IL-5,
and IL-6 completely canceled the RA-mediated ALP activation. On the
other hand, the RA-induced ALP activation was additionally enhanced
with IL-1
(10 ng/ml) and IL-1
(1 ng/ml); the activity increased
9- and 16-fold, respectively, compared with that of vehicle-treated
control cells. In the absence of RA, none of these cytokines or growth
factors changed the ALP activity in IEC-6 cells (data not shown).
|
Effect of RA and IL-1 on growth of IEC-6 cells.
When IEC-6 cells were cultured in 5% FCS-containing DMEM, the number
of IEC-6 cells linearly increased over 5 days, and the treatment with 1 µM RA significantly inhibited the cell growth by ~25%. The
simultaneous treatment with 1 ng/ml IL-1
and 1 µM RA suppressed
the cell growth to ~50% of that of control cells, although IL-1
(1 ng/ml) did not affect the cell growth of IEC-6 cells cultured in 5%
FCS-containing DMEM (Fig. 1D). Hematoxylin-eosin staining
showed that RA- and IL-1
-treated cells became spindle shaped (data
not shown). Therefore, the morphological changes were further examined
by transmission electron microscopy. Treatment with RA and IL-1
appeared to stimulate the development of rough endoplasmic reticulum;
however, the cells treated with RA and IL-1
did not exhibit
morphological features characteristic of absorptive cells such as
microvilli formation (data not shown).
Stimulatory effect of IL-1 on RA-mediated LBK ALP expression in
IEC-6 cells.
Western blot analysis showed that RA-treated IEC-6 cells contained a
75-kDa protein corresponding to rat LBK ALP (Fig.
2A). IL-1
further
enhanced the RA-mediated increase in LBK ALP protein, whereas the
IL-1
itself did not induce LBK ALP protein in IEC-6 cells (Fig.
2A). Intestinal ALP protein was not detected in IEC-6 cells
even after simultaneous treatment with RA and IL-1
(data not shown).
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Changes in RAR and RXR mRNA levels in IEC-6 cells treated with RA
and IL-1.
Northern blot analyses showed that the mRNAs of RAR-
, RAR-
, and
RXR-
were expressed at higher levels in IEC-6 cells, similarly to F9
cells (Fig. 3). In
contrast, IEC-6 cells contained the transcripts of RAR-
, RXR-
,
and RXR-
at low concentrations. RA significantly increased the
concentrations of RAR-
and -
mRNAs. IL-1
also upregulated the
expression of RAR-
and RXR-
mRNAs in a time-dependent manner, whereas it did not change the levels of other receptor transcripts. When IEC-6 cells were treated with both RA and IL-1
, the expressions of
- and
-isoform transcripts of both RAR and RXR
were enhanced. Among these changes, the upregulation of RAR-
and
RXR-
mRNA expression most rapidly occurred within 4 h after treatment with RA and IL-1
.
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Type 1 IL-1 receptor mRNA in IEC-6 cells.
It has been reported that immature rat small intestinal epithelial
cells such as IEC-18 cells expressed low levels of the type 1 IL-1
receptor mRNAs, which were detected by RT-PCR but not by Northern blot
analysis (26). Therefore, we measured the levels of type 1 IL-1 receptor mRNA in IEC-6 cells by a semiquantitative RT-PCR. The
type 1 IL-1 receptor mRNA was linearly amplified from 25 to 34 cycles
of PCR (data not shown). Treatment with RA and/or IL-1 did not
change the ratio of type 1 IL-1 receptor mRNA to
-actin mRNA, as
shown in Fig. 4.
|
RXRE-binding activity in IEC-6 cells.
Gel mobility shift assay showed that vehicle-treated IEC-6 cells did
not have any specific RXRE-binding activity (Fig.
5). RA produced RXRE-binding activity in
IEC-6 cells on days 1 and 3 (Fig. 5). In the absence of RA,
IL- did not produce the RXRE-binding activity on day 1,
whereas it enhanced the RA-mediated RXRE-binding activity (Fig. 5).
This binding activity was inhibited by addition of excess unlabeled
RXRE oligonucleotide but not by the mutant RXRE oligonucleotide (Fig.
5).
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Effect of protein kinase inhibitors on ALP activity.
We examined whether protein kinases were involved in the interaction
between IL-1 and RA on ALP induction. A high concentration (20 µM)
of a protein kinase A (PKA) inhibitor, H-8, was required to
significantly inhibit the induction of ALP activity with IL-1
plus
RA (Fig. 6), and H-8 at this
concentration suppressed the induction by only 13%. In contrast,
protein kinase C (PKC) inhibitors H-7 and GF-109203X more effectively
inhibited the increase in ALP activity. Twenty micromolar H-7 or five
micromolar GF-109203X completely suppressed the synergistic activation
with RA and IL-1
, and the levels returned to those of RA-treated
IEC-6 cells. Cell viability assessed by trypan blue exclusion and
adherence to the culture plates was maintained throughout the
experiments (data not shown).
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DISCUSSION |
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IEC-6 cells may be a useful model to study the regulation of LBK
ALP expression in normally developing fetal small intestine because
they have features characteristic of fetal small intestinal epithelial
cells (20, 23). In the present study, we examined the
interaction between RA and several cytokines and growth factors on ALP
activity in IEC-6 cells. Among the cytokines and growth factors tested,
only IL-1, especially IL-1, synergistically increased the
RA-mediated upregulation of bone-type ALP expression in IEC-6 cells,
suggesting that IL-1 may be a potent endogenous regulator for the
bone-type isozyme expression in fetal rat small intestine. Several
investigations have suggested that IL-1 is one of the important
cytokines for the regulation of gene expression in fetal tissues. For
example, IL-1 released from placenta could upregulate metallothionein
expression in the fetal liver (8) and regulate glucocorticoid levels by stimulating the release of adrenocorticotropic hormone from fetal pituitary gland (3). IL-1 may interact
with RA, a exogenous morphogen, to upregulate the expression of
bone-type ALP in the fetal rat small intestine. In contrast, EGF and
ILs-2, -4, -5, and -6 completely inhibited the RA-mediated increase in ALP activity, although M-CSF, TGF-
, and TNF-
did not affect it.
EGF, IL-2, and IL-4 are known to be potent mitogens for IEC-6 cells
(17, 20, 25). It is possible to speculate that
proliferation signals induced by these factors may interfere with
RA-mediated expression of bone-type ALP in IEC-6 cells.
IL-1 itself could not stimulate bone-type ALP expression, and it
could augment this expression only when RA-mediated pathways were
active, suggesting that IL-1
may act as a cofactor that specifically
enhances the distinct RA signaling pathway in IEC-6 cells.
Lipopolysaccharide and vitamin D3 have been shown to
exhibit similar stimulatory effects on RA-mediated ALP activity in
IEC-6 cells (5, 11). However, those studies evaluated the
effects by measuring ALP activity; therefore, the molecular
mechanism(s) underlying the interaction is not fully understood. At
first, we examined whether the stimulatory effect of IL-1
on the RA action occurred at the level of the membrane receptor or nuclear receptors. Treatment with IL-1
and/or RA did not change the
expression of type 1 IL-1 receptor transcript, although it was reported
that stimulation of the IEC-6 cells by IL-1
downregulated the
expression of type 1 IL-1 receptor at 24 h (18). We
also examined the changes in RAR and RXR transcript expressions.
IL-1
alone significantly increased the level of RAR-
and RXR-
mRNAs, and it also enhanced the RA-mediated expression of these
receptors. Among the changes in expressions of all retinoid receptors
tested, RAR-
and RXR-
mRNAs responded most rapidly to the
simultaneous treatment within 4 h, and their enhanced expressions
were well correlated with the expression of bone-type ALP. The present
study also demonstrated that IL-1
further enhanced the RA-mediated
increase of the binding activity to an RXRE, at which a homodimer of
RXR or heterodimer of RAR and RXR can interact (4). These
results indicate that IL-1
may stimulate the RA-mediated signaling
pathway by upregulating the RAR-
- and/or RXR-
-dependent
transcription cascade.
An apparent retinoic acid receptor response element (RARE) has not been
documented in the 5'-flanking regions of exon 1 (bone type) and exon 2 (liver type) of rat LBK ALP gene (28). An RXRE is located
in the upstream of the liver-type exon, but not the bone-type exon, of
rat LBK ALP gene (28). Although an RARE or RXRE has not
been reported to be present in the 5'-flanking region of exon 1A
(corresponding to rat exon 1) of mouse LBK ALP gene, RA has also been
shown to induce LBK ALP protein by increasing the amount of the
mRNA-containing exon 1A in mouse F9 teratocarcinoma cells
(26). Thus the upregulation of RAR- and RXR-
mRNA
expressions and the activation of RXRE binding may evoke the secondary
responses required for bone-type ALP expression rather than directly
stimulating the transcriptional activation of the ALP gene. At present,
the underlying mechanism for the retinoid receptor-mediated
transcription of the rat bone-type ALP gene remains to be elucidated.
We next examined whether protein kinases were involved in the
stimulatory effect of IL-1 on RA-mediated ALP expression because protein kinase inhibitors suppressed the synergistic effects between peptide growth factors and nuclear hormones and catalytic molecules downstream of both receptors are usually phosphorylated by protein kinases for their activation (1, 9, 31). Several recent investigations reported that a cAMP response element as well as RARE
was involved in RA-dependent RAR-
promoter activation in embryonal
carcinoma cells (13) and that cAMP response element binding protein is known to be activated by PKA (15).
However, a high concentration (20 µM) of a PKA inhibitor, H-8, was
required to significantly inhibit the increased ALP activity by 13%.
Furthermore, dbcAMP did not affect ALP activity in IEC-6 cells even in
the presence of IL-1
or RA (data not shown), suggesting that PKA may
not be involved in the interaction between IL-1
and RA in IEC-6
cells. In contrast, relatively specific PKC inhibitors, H-7 and
GF-109203X, significantly suppressed the synergism between IL-1
and
RA on ALP activity at the lower concentrations. IL-1 is known to
increase PKC activity in various types of cells, such as human
astroglioma cells (2), mouse osteoblast-like cells (10), and mouse fibroblast cells (29).
Furthermore, Kurie et al. (14) reported that the
stimulation of PKC by phorbol ester could upregulate RAR-
expression
and potentiate the effects of RA on RAR-
-mediated transcription
(14). On the basis of this information, PKC may be one of
the putative mediators for the interaction between IL-1
and RA
signaling pathways in IEC-6 cells.
At present, we do not know whether RA similarly regulates transcription of distinct genes by interacting with growth factors and/or cytokines in vivo. However, our results suggest that overproduction of inflammatory cytokines under specific situations, such as infection and inflammation, may greatly modify RA-dependent gene expression; therefore, it may disturb the normal development of tissues including the small intestine.
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ACKNOWLEDGEMENTS |
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We thank P. Chambon, Laboratoire de Genetique Moleculaire des Eucaryotes U.184, Centre National de la Recherche Scientifique, Strasbourg, France, who kindly provided plasmids containing RAR and RXR cDNAs.
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FOOTNOTES |
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This work was supported by a Grant-in Aid for Scientific Research from The Ministry of Education, Science, Sports and Culture, Japan (to T. Nikawa).
Address for reprint requests and other correspondence: T. Nikawa, Dept. of Nutrition, School of Medicine, Univ. of Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan (E-mail: nikawa{at}nutr.med.tokushima-u.ac.jp).
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.
Received 27 April 2000; accepted in final form 22 August 2000.
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