Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
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ABSTRACT |
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Thyroid hormones are important for
mammary gland growth and development. The iodothyronine deiodinases
play a key role in thyroid hormone metabolism. We have showed that type
II 5'-deiodinase (5'D2) activity and mRNA are present in the mouse
mammary gland and that their levels are reduced in the lactating gland.
To investigate the regulatory mechanism of mouse 5'D2 gene
(mdio2) expression in mammary epithelium, we employed the
HC11 cell line, which is derived from mouse mammary epithelial cells
and retains the ability to express differentiated function. HC11 cells
were treated with combinations of insulin, glucocorticoid (GC,
dexamethasone), prolactin, and epidermal growth factor (EGF), and 5'D2
activity and the D2-to-GAPDH mRNA ratio were measured by
125I release from 125I-labeled
thyroxine and semiquantitative RT-PCR, respectively. EGF increased both
5'D2 activity and mRNA levels about twofold. GC reduced both 5'D2
activity and mRNA in a dose-dependent manner, and their levels were
decreased to approximately one-tenth and one-fifth, respectively, of
control levels. These data demonstrated that mdio2
expression in HC11 cells is upregulated by EGF mainly at the
pretranslational level and downregulated by GC at both pre- and
posttranslational levels. Furthermore, we showed that GC reduced the
promoter activity of the 627- bp 5'-upstream region of the
mdio2/luciferase chimeric reporter gene, suggesting that GC
exerts its effect, at least in part, at the transcriptional level.
type II iodothyronine deiodinase; HC11 cells; mammary gland; epithelial growth factor; promoter activity
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INTRODUCTION |
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THE GROWTH AND DEVELOPMENT of the mammary gland are regulated by synergic action of hormones and growth factors, such as prolactin (PRL), glucocorticoid (GC), insulin, placental lactogen, and epidermal growth factor (EGF) (24, 25, 33). Thyroid hormones (TH) are also important for mammary growth and development (32, 34, 36). It has been reported that TH-specific binding is present in the nucleus as well as in the cytosol fraction in mouse mammary tissue (28). TH stimulate mammary gland growth and development in vivo as well as in vitro (34, 36). Administration of thyroxine (T4) to pregnant and lactating rats increases the synthesis of milk proteins in the mammary gland (26). On the other hand, administration of an excess amount of 3,3',5-triiodothyronine (T3) to pregnant and lactating rats decreases milk production (20). These results are not consistent and thus need to be clarified to determine the importance of T3 production within the mammary gland.
The iodothyronine deiodinases are important for the metabolism of TH (6, 18, 19). 5'-Deiodinase (5'D), which catalyzes T4 to the most active form, T3, has two distinct isoforms, type I (5'D1) and type II (5'D2). 5'D1 has a high Km value, whereas 5'D2 exhibits a higher catalytic activity (17, 19, 35). It has been reported that 5'D1 activity and mRNA are present in the lactating rat mammary gland (2, 23). Although another report showed that 5'D1 was expressed in the lactating mouse mammary gland, 5'D1 activity was at a very low level compared with that in the rat (7). On the other hand, 5'D2 is the predominant form in the lactating cow and pig mammary gland (16, 29). Our previous study (31) has shown that 5'D2 activity and mRNA are present in the mouse mammary gland and that their levels in the lactating mouse mammary gland are lower than those in the virgin and pregnant animals. Studies of the mechanism regulating 5'D should provide useful information for the function and metabolism of TH in the mammary gland.
The HC11 cell line, which is derived from epithelial cells of the
BALB/C mouse mammary gland, exhibits the ability to differentiate and
produce a major milk protein, -casein, in response to the lactogenic
hormones insulin, GC, and PRL (4). In the present study,
we employed this cell line to investigate the hormonal control of 5'D2
activity and mRNA. We found that EGF upregulated mouse 5'D2 gene
(mdio2) expression mainly at the pretranslational level and
that GC downregulated mdio2 expression at both pre- and
posttranslational levels in HC11 cells. Furthermore, we showed that GC
downregulated the promoter activity of the 5'-upstream region of
mdio2 in HC11 cells, suggesting the transcriptional regulation of mdio2 expression by GC.
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MATERIALS AND METHODS |
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Materials.
Bovine PRL and mouse EGF were obtained from the Hormone Distribution
Program (National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health) and Upstate Biotechnology
(Waltham, MA), respectively. T4, T3, and
6 n-propyl-2-thiouracil (PTU) were purchased from Sigma (St.
Louis, MO). [125I]T4 (862-1,250
µCi/µg) and 125I-labeled reverse T3
([125I]rT3) (762-1,250 µCi/µg) were
from New England Nuclear (Boston, MA). [-32P]dATP and
[
-32P]dATP (6,000 µCi/mmol) were obtained from
Amersham Pharmacia Biotech (Piscataway, NJ). Other chemicals were
commercial products of reagent grade.
Cell culture. HC11 cells were grown in RPMI 1640 medium supplemented with 10% heat-inactivated fetal calf serum (FCS; Life Technologies, Rockville, MD), antibiotics, 5 µg/ml insulin, and 10 ng/ml EGF (4). Cells were propagated on 60-mm dishes or 6-well plates for 5'D assay or RNA preparation, respectively. Two days after reaching confluence, cells were treated with various combinations of 5 µg/ml insulin, 10 ng/ml EGF, 5 µg/ml PRL, and 1 µM dexamethasone in RPMI 1640 medium supplemented with 10% FCS for 2 days. Some cells were treated without hormones and EGF and used as controls.
5'D assay.
HC11 cells were washed twice with cold PBS, harvested, sonicated in a
buffer (0.25 M sucrose in 0.02 mM Tris buffer, pH 7.4, containing 1 mM
EDTA and 10 mM DTT), and stored at 70°C. The protein concentration
of sonicates was measured by a protein assay kit (Bio-Rad Laboratories,
Hercules, CA). 5'D2 assay was performed as described previously
(31). Briefly, the substrate,
[125I]T4, was purified using an AG50W-X8
column (Bio-Rad Laboratories). Samples (50-150 µg protein), 0.1 M phosphate buffer (pH 7.0), 2 nM [125I]T4
(~2 × 105 counts/min), 1 mM EDTA, 25 mM DTT, and 1 mM PTU in a final volume of 500 µl were incubated at 37°C for
3 h. The release of 125I
in the reaction
mixture was measured after it was passed through a small AG50W-X8
column. Background controls containing no enzyme sample were always
included in the assay, and net radioactivity was determined by
subtracting the value obtained by background controls from that by
enzyme samples. 5'D2 activity is expressed as femtomoles per milligram
protein per hour. The amount of 125I
released
was <30% of total radioactivity in the reaction mixture. The
125I
release was linear for 6 h and also
linear with increasing protein concentrations. 5'D1 activity was
assayed using 2 nM [125I]rT3, 0.5 µM
nonradiolabeled rT3, and other reagents as described (1).
RNA preparation and RT-PCR analysis.
Total RNA was isolated using TRIzol Reagent (Life Technologies)
according to the manufacturer's instructions. RT-PCR was carried out
with an RT-PCR kit obtained from Perkin-Elmer (Foster City, CA), as
described previously (31). Briefly, 2 µg of total RNA were reverse-transcribed using random hexamers and MuLV reverse transcriptase in a 40-µl reaction volume at 42°C for 30 min. Five microliters of these reactions were then used in PCR in a 25-µl volume of reaction mixture under the following conditions: 1 cycle of
95°C × 1 min, 34 cycles of 94°C × 30 s,
57°C × 40 s, 72°C × 1 min, and a final 10-min
extension period, except for GAPDH, which was performed for 22 cycles.
Primers used were as follows: mouse 5'D1 sense primer,
5'-GCACCTGACCTTCATTTCTT-3'; antisense primer,
5'-CTGGCTGCTCTGGTTCTG-3' (GenBank accession no. MMU49861) (21); mouse 5'D2 sense primer, 5'-ACTCGGTCATTCTGCTCAAG-3';
antisense primer, 5'-TTCAAAGGCTACCCCGTAAG-3' (AF093137, AF096875) (10, 31); mouse type III deiodinase (D3) sense primer,
5'-CTAGGCACGGCCTTCATGCTCTGGC-3'; antisense primer,
5'-ATCATAGCGCTCCAACCAAGTGCGC-3' (AF426023) (11).
Mouse -casein primers were 5'-ACTACATTTACTGTATCCTCTGA-3' and
5'-GTGCTACTTGCTGCAGAAAGTACAG-3' (X04490) (37). The primer set for GAPDH was purchased from Clontech (Palo Alto, CA). PCR products
were analyzed by electrophoresis on a 1.5% agarose gel containing
ethidium bromide. RT-PCR without reverse transcriptase and PCR using
H2O as a template were carried out as negative controls.
Reporter gene assay. The genomic fragment containing 888 bp of the 5'-upstream region and 25 bp of the 5'-untranslated region (UTR) of the mouse 5'D1 gene (mdio1) was obtained by PCR using Pfu DNA polymerase and the primers 5'-TCTAGATGATTCTACACTCTCTTCTGATCTCC-3' and 5'-AGCAGATCTTCAGCACGGGGCAGAAGTGGTC-3' (MMU49862) (21). The PCR products were cut by BglII, cloned into pGL3-Basic vector (Promega, Madison, WI) at the SmaI/BglII site, and named pGL3-D1. The mdio2 reporter construct pGL3-D2, containing 627 bp of the 5'-upstream region and 26 bp of the 5'-UTR, was obtained as described previously (30).
For transient transfection experiments, ~5 × 105 HC11 cells per well were cultured on 6-well plates 1 day before transfection. One microgram of reporter construct was cotransfected with 100 ng of an internal control, pRL-TK (Promega), by use of Lipofecto Amine Plus (Life Technologies), according to the manufacturer's instructions. Two days after transfection, cells were washed with PBS and treated with or without the combination of hormones and EGF, as described above. Luciferase assay was performed with the Dual-Luciferase kit (Promega) 48 h after treatment. The luciferase activity of the reporter gene was normalized by that of pGL3-Basic vector in each of the treated cells. pGL3-Promoter vector (Promega) containing an SV40 promoter was used as a positive control.Statistical analysis. Data were examined by Student's t-test or by ANOVA, followed by Schemes's post hoc test when it was appropriate. A level of P < 0.05 was accepted as statistically significant. Data are presented as means ± SE.
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RESULTS |
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5'D activity and mRNA in HC11 cells.
Initially, we examined 5'D activity in HC11 cells treated with insulin
and EGF (IE) or with the combination of insulin, dexamethasone, and PRL
(IDP). IE-treated cells had 5'D2 activity at the level of 137.1 ± 32.4 fmol · mg
protein1 · h
1,
whereas IDP-treated cells exhibited only 3.4% of 5'D2 activity in
IE-treated cells (Fig. 1). The enzyme
activity of HC11 cell extracts was decreased by 1 µM aurothioglucose
(18.1 ± 9.1%) but not by 1 mM PTU (100 ± 5.4%) when added
to the reaction mixture. No 5'D1 activity was detected in either IE- or
IDP-treated cells. These data indicate that HC11 cells, like mammary
glands of mouse, cow, and pig (16, 31), possess 5'D2
activity that can be downregulated by IDP treatment.
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Effects of lactogenic hormones and EGF on 5'D2 activity and mRNA in
HC11 cells.
To clarify which hormones or growth factor regulate
mdio2 expression, HC11 cells were treated with various
combinations of EGF and the lactogenic hormones insulin, dexamethasone,
and PRL, and 5'D2 activity and the D2/GAPDH mRNA ratio were measured
(Fig. 3). In control cells treated
without hormones and EGF, 5'D2 activity and the D2/GAPDH mRNA ratio
were 72.2 ± 20.0 fmol · mg
protein1 · h
1 and
0.410 ± 0.050, respectively. Addition of EGF increased both 5'D2
activity and the D2/GAPDH mRNA ratio about twofold (control vs. EGF and
insulin vs. IE), suggesting that EGF upregulates mdio2 expression mainly at a pretranslational level. This effect of EGF was
apparent at concentrations higher than 1 ng/ml (data not shown). On the
other hand, addition of dexamethasone decreased 5'D2 activity to <10%
and lowered the D2/GAPDH mRNA ratio to 20-30% of corresponding
controls (control vs. dexamethasone, insulin vs. insulin + dexamethasone, PRL vs. dexamethasone + PRL, and insulin + PRL
vs. IDP). Addition of insulin or PRL did not change the level of 5'D2
activity or the D2/GAPDH mRNA ratio.
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mdio2 Promoter activity in HC11 cells.
To assess whether the effects of EGF and dexamethasone on
mdio2 expression in HC11 cells are manifested at the level
of transcription, we investigated the promoter activity of
mdio2 in IE- and IDP-treated cells by transient transfection
experiments. As shown in Fig. 5A, the pGL3-D2 construct
(nucleotides 627 to +26 of mdio2) exhibited promoter
activity (17.8 ± 0.4-fold of pGL3-Basic) in IE-treated cells.
This promoter activity was significantly decreased by IDP treatment. On
the other hand, the pGL3-D1 construct (nucleotides
888 to +25 of
mdio1) showed little promoter activity, whereas pGL3-Promoter showed a high promoter activity in both IE- and IDP-treated HC11 cells. These data indicate that mdio2
promoter activity is present in HC11 cells and that the difference
of this promoter activity between IE and IDP treatment is specific.
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DISCUSSION |
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In this study we have demonstrated that 5'D2 activity and mRNA are present in HC11 cells and that their levels are reduced in response to the lactogenic hormones insulin, GC, and PRL. These responses are similar to those of mouse mammary gland, the mdio2 expression of which is reduced during lactation (31). These results suggest that HC11 cells can serve as a model for investigation of the regulatory mechanism of mdio2 expression in the mammary gland.
Administration of an excess amount of T4 increases
the synthesis of milk protein in the mammary gland (26),
but administration of an excess amount of T3 decreases milk
production (20). Physiological concentrations of
T3 stimulate lobulo-alveolar development and PRL-induced
synthesis of milk products in organ culture, but high concentrations of
T3 are inhibitory (34). The mammary gland probably requires different amounts of intracellular T3 in
each reproductive stage. Levels of 5'D2 activity and mRNA are lower in
the lactating mouse mammary gland than in the virgin or pregnant mouse
(31). IDP treatment, which induces cell
differentiation and production of -casein, reduced mdio2
expression in HC11 cells. It has been reported that the intracellular
supply of T3 is dependent on conversion from T4
to T3 by 5'D2 in astroglial cells (9). We
speculate that the lactating mouse mammary gland needs only a low but
adequate amount of T3, which is mainly regulated by 5'D2.
EGF upregulated both 5'D2 activity and mRNA to a similar extent,
suggesting pretranslational regulation. However, EGF failed to increase
the luciferase activity of the pGL3-D2 construct (nucleotides 627 to
+26 of mdio2), suggesting that the 627-bp 5'-upstream region
of mdio2 does not contain the element responsible for 5'D2 upregulation by EGF. We could not rule out the possibility that the
farther upstream region may contain an EGF-responsive element. Alternatively, EGF may increase the stability and/or decrease the
degradation of 5'D2 mRNA. It has been reported that EGF induces D3
activity and mRNA in cultured rat brown adipocytes (12,
13). The studies of the effect of EGF on each type of deiodinase
in different tissues will be needed to understand the regulatory mechanism of deiodinases and TH.
GC alone or in combination with insulin and/or PRL downregulated
mdio2 expression in HC11 cells at both pre- and
posttranslational levels. It has been reported that GC induces 5'D1
activity in mouse liver and both 5'D1 activity and mRNA in rat
hepatocytes (22, 27). GC reduces 5'D2 activity in human
cultured placental cells (14). These opposite effects of
GC on 5'D1 and 5'D2 gene expression are similar to those of TH,
T4, and T3, which increase 5'D1 but reduce 5'D2
(17, 35). GC and TH may interact to regulate 5'D1 and 5'D2
expression. The reporter assay using the proximal promoter region of
mdio2 indicated transcriptional downregulation of
mdio2 expression by GC. Protein-protein interactions between the GC receptor and GATA-1 (8) and between the GC
receptor and cAMP response element-binding protein (15)
have been reported. In these cases, GC response elements are found near
the GATA or cAMP response element. In some genes, such as the
-subunit of glycoprotein hormones, GC negatively regulates the
transcription without consensus sequence to the GC response elements in
their 5'-upstream regions (5). It has been reported that
the 5'-upstream region of mdio2 contains potential GATA and
cAMP response elements but not the GC response element
(30). The sequence(s) in mdio2 responsible for
downregulation by GC needs to be identified. In addition, it has been
reported that a GC inhibitor suppresses the induction of 5'D2 activity
in response to cold stress in the rat adrenal gland (3).
These results suggest that the mode of regulation of 5'D2 by GC may
vary among different tissues.
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ACKNOWLEDGEMENTS |
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We thank Dr. Jacob Robbins, NIDDK, NIH, for helpful discussions and valuable comments.
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. Oka, National Institutes of Health, Bldg. 8, Rm. 118, 9000 Rockville Pike, Bethesda, MD 20892 (E-mail: OkaT{at}bdg8.niddk.nih.gov).
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.
First published February 11, 2003;10.1152/ajpendo.00571.2002
Received 26 December 2002; accepted in final form 4 February 2003.
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