Regulation of type II deiodinase expression by EGF and glucocorticoid in HC11 mouse mammary epithelium

Shigeaki Song and Takami Oka

Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892


    ABSTRACT
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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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


    INTRODUCTION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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, beta -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.


    MATERIALS AND METHODS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
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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). [alpha -32P]dATP and [gamma -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 beta -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.

Semiquantitative RT-PCR analysis was performed by the method described previously (31). RT-PCR was carried out as described above, with 5 pmol of each primer set for mouse 5'D2 and GAPDH in one tube for 20 cycles. 5'D2 sense and GAPDH sense primers were 5'-end labeled with [gamma -32P]dATP. At least one sample in each group was applied to PCR for 18-22 cycles to confirm that the amplification of the products increased exponentially with respect to the PCR cycles. PCR products were electrophoresed on a 3.5% polyacrylamide gel. After autoradiography, each band of PCR products corresponding to 5'D2 and GAPDH was cut, and the radioactivities were counted. The radioactivities of the 5'D2 band were normalized to those of the GAPDH band and expressed as a 5'D2-to-GAPDH (D2/GAPDH) mRNA ratio. The amount of 32P incorporation into each PCR product was <10% of total radioactivity of each primer added in the reaction mixture.

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.


    RESULTS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
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 protein-1 · 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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Fig. 1.   Type II 5'-deiodinase (5'D2) activity in HC11 cells. HC11 cells were treated in the presence of 5 µg/ml insulin and 10 ng/ml epidermal growth factor (EGF) (IE) or 5 µg/ml insulin, 1 µM dexamethasone, and 5 µg/ml prolactin (PRL) (IDP) for 2 days. Cell sonicates were assayed for 5'D activity as described in MATERIALS AND METHODS. Values are means ± SE (n = 7/group). *P < 0.005.

We performed RT-PCR analysis for mouse 5'D1, 5'D2, and D3 mRNA in HC11 cells. A clear band for 5'D2 was observed in both IE- and IDP-treated cells (Fig. 2A, top). 5'D1 mRNA was also detected, but the intensity of the band was much weaker than that of 5'D2 bands (data not shown), whereas D3 mRNA was not detected in those cells under the conditions used (data not shown). Northern blot analysis for mouse 5'D2 mRNA was also performed, as described previously (30, 31), using poly(A)+ RNA from cultured cells. The presence of a faint band, ~7.9 kb in length, was detected in IE- but not IDP-treated cells (data not shown). These data indicate that 5'D2 mRNA is present as a predominant type of 5'D in HC11 cells. Similar results were obtained in the previous studies of 5'D in the mammary gland of mouse, cow, and pig (16, 31). Figure 2A (middle) also showed that mouse beta -casein mRNA was induced by IDP but not by IE treatment, as previously reported (4).


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Fig. 2.   RT-PCR analysis of mouse 5'D2 mRNA in HC11 cells. A: RT-PCR was performed using total RNA from HC11 cells treated with IE or IDP, as described in Fig. 1. Primers used were either of a mouse 5'D2 (D2, 590 bp), beta -casein (538 bp), or GAPDH (953 bp) primer set. Lane M, DNA molecular weight marker. Lanes 1 and 2, IE-treated cells with or without RT, respectively. Lanes 3 and 4, IDP-treated cells with or without RT, respectively. Lane 5, H2O with all of the PCR reagents. Lane 6, positive controls for RT-PCR, mouse brain, and lactating mouse mammary gland for 5'D2 and beta -casein, respectively. B: semiquantitative RT-PCR was carried out using 32P-labeled 5'D2 sense primer [3 × 106 counts · min-1 (cpm) · 5 pmol-1] and GAPDH sense primer (6 × 104 cpm/5 pmol), as described in MATERIALS AND METHODS. PCR products for 5'D2 and GAPDH were separated by polyacrylamide gel electrophoresis. Lanes 1 and 2, IE-treated cells with or without RT, respectively. Lanes 3 and 4, IDP-treated cells with or without RT, respectively. Lane 5, H2O with all of the PCR reagents. C: relative level of 5'D2 mRNA. Radioactivities of the 5'D2 band were normalized against the corresponding value of the GAPDH band used in each reaction and were expressed as means ± SE (n = 4/group). *P < 0.05.

Semiquantitative RT-PCR technique was used to investigate the level of 5'D2 mRNA in HC11 cells. As shown in Fig. 2, B and C, the D2/GAPDH mRNA ratio in IDP-treated cells was 18.4% of that in IE-treated cells. These results indicate that IDP treatment induces beta -casein mRNA and reduces 5'D2 mRNA in HC11 cells.

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 protein-1 · 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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Fig. 3.   Effects of lactogenic hormones and EGF on 5'D2 activity and mRNA in HC11 cells. HC11 cells were treated with the indicated combinations of 5 µg/ml insulin (I), 10 ng/ml EGF (E), 1 µM dexamethasone (D), and 5 µg/ml PRL (P) for 2 days. 5'D2 activity and the D2/GAPDH mRNA ratio were determined as described in Figs. 1 and 2 and were normalized to the level obtained from control cells treated without hormones and EGF (C). Values are means ± SE (n = 3-7/group). Superscript letters a-d indicate a significant difference compared with control (P < 0.05).

As shown in Fig. 4, the inhibitory effect of dexamethasone on 5'D2 activity was concentration dependent. 5'D2 activity decreased ~40% in the presence of 10-9 M dexamethasone and reached the lowest level, 4.0 ± 2.7% of the control, in the presence of 10-7 M dexamethasone. On the other hand, the level of the D2/GAPDH mRNA ratio was decreased only 15% in the presence of 10-9 M dexamethasone and reached the lowest level, 41.6 ± 3.4% of control, at 10-8 M dexamethasone. These data suggest that dexamethasone downregulates mdio2 expression at both pre- and posttranslational levels.


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Fig. 4.   Effects of various concentrations of dexamethasone on 5'D2 activity and mRNA in HC11 cells. HC11 cells were treated with the indicated concentrations of dexamethasone for 2 days. Control, no dexamethasone treatment. 5'D2 activity and the D2/GAPDH mRNA ratio were determined as described in Figs. 1 and 2 and were normalized to levels obtained from control cells. Values are means ± SE (n = 4/group). Superscript letters a-c indicate a significant difference compared with control (P < 0.05).

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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Fig. 5.   Promoter activity of the 5'-upstream region of mdio1 and mdio2 in HC11 cells. A: one microgram of pGL3-D1 or pGL3-D2 (mdio1 or mdio2/luciferase chimeric reporter gene, respectively) was transiently transfected into HC11 cells. Two days after transfection, cells were treated with either IE or IDP, as described in Fig. 1, for 2 days. Luciferase activity was measured and expressed as fold induction of the pGL3-Basic, promoterless vector, in each treatment. The pGL3-Promoter vector was used as a positive control. Transfection efficiency was normalized by cotransfection of pRL-TK. Values are means ± SE of 3 duplicate experiments. *P < 0.001. B: one microgram of pGL3-D2 was transiently transfected into HC11 cells. Two days after transfection, cells were treated with the indicated combinations of hormones and EGF, as described in Fig. 3, or without hormones and EGF (C) for 2 days. Luciferase activity was measured and expressed as described above. Values are means ± SE from 3 dishes. *P < 0.05 compared with C, IE, and E treatment.

Promoter activities of the pGL3-D2 construct were examined in HC11 cells treated with combinations of insulin, dexamethasone, PRL, and EGF (Fig. 5B). The treatment with IE or EGF alone did not change mdio2 promoter activity compared with control cells treated without hormones and EGF. Dexamethasone significantly decreased the promoter activity to a lower level, similar to that obtained by IDP treatment. These data indicate that dexamethasone downregulates mdio2 expression, at least in part, at a transcriptional level. They also suggest that the proximal promoter (nucleotides -627 to +26) of mdio2 contains the element(s) responsible for this downregulation.


    DISCUSSION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
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 beta -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 alpha -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.


    ACKNOWLEDGEMENTS

We thank Dr. Jacob Robbins, NIDDK, NIH, for helpful discussions and valuable comments.


    FOOTNOTES

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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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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Am J Physiol Endocrinol Metab 284(6):E1119-E1124




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