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First Department of Internal Medicine, Gunma University School of Medicine, Maebashi 371-8511, Japan
Address all correspondence and requests for reprints to: Masami Murakami, M.D., First Department of Internal Medicine, Gunma University School of Medicine, Maebashi 371-8511, Japan. E-mail: mmurakam{at}showa.gunma-u.ac.jp
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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with a constitutive activation of cAMP production in
cultured cells, and six cases with papillary thyroid carcinoma were
analyzed in the present study. Free T3 was increased,
whereas free T4 was within the normal range in all patients
with hyperfunctioning thyroid adenoma. Thyroid tumor tissue and
surrounding nontumor tissue were obtained at the time of surgery, and
DII expression was compared between tumor tissue and nontumor tissue in
each case. Northern analysis demonstrated the presence of DII messenger
RNA (mRNA) approximately 7.5 kb in size in all of the tumor and
nontumor tissues. DII mRNA and DII activity in hyperfunctioning thyroid
adenoma were significantly increased compared with those in nontumor
tissue in each case. In contrast, DII mRNA and DII activity in
papillary thyroid carcinoma were decreased compared with those in
nontumor tissue in each case. DII mRNA and DII activity in cultured
human thyroid cells were significantly stimulated by TSH in a
dose-dependent manner. The promoter activity of the human DII gene
including the complete cAMP response element, transfected to cultured
human thyroid cells, was stimulated by (Bu)2cAMP.
In summary, these results suggest that DII expression in human thyroid
gland is regulated at the transcriptional level through the TSH
receptor-Gs-cAMP regulatory cascade, which may be
related to the increase in circulating T3 level in patients
with Graves’ disease and hyperfunctioning thyroid adenoma.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently, a complementary DNA (cDNA) encoding DII was cloned from Rana catesbeiana tissues (2), and its mammalian counterpart was isolated (3). Subsequently, DII messenger RNA (mRNA) was unexpectedly detected in thyroid gland, skeletal muscle, and heart in humans (4, 5). DII mRNA levels were reported to be especially high in thyroids from patients with Graves’ disease and in follicular thyroid adenomas (4). These observations suggest previously unrecognized roles of DII in those tissues, including a possible contribution to circulating T3 levels (4, 5). It appears, therefore, important to study the mechanisms involved in the regulation of DII expression in those tissues.
In the present report we analyzed DII expression in thyroid tumor tissues and normal surrounding tissues from patients with hyperfunctioning thyroid adenoma and papillary thyroid carcinoma and studied the regulation of DII expression in cultured human thyroid cells to elucidate the mechanisms involved in the regulation of DII expression in human thyroid gland.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows the profiles of
patients with thyroid tumor studied in the present report. Three
patients (cases 1–3) with hyperfunctioning thyroid adenoma and six
patients (cases 4–9) with papillary thyroid carcinoma were studied.
All of the patients with hyperfunctioning thyroid adenoma were
demonstrated to have hot nodules by 123I
scintigraphy. In case 1, primary culture of the cells from
hyperfunctioning thyroid adenoma which showed an activating mutation of
Gs and that of the cells from surrounding
nontumor tissue were performed. As previously described, constitutive
activation of cAMP production was demonstrated in cultured cells
obtained from hyperfunctioning thyroid adenoma tissue compared with the
cells from surrounding nontumor tissue in this case (6).
Informed consent was obtained from the patients for the use of thyroid
tumor tissues. Use of the tissues did not adversely affect the clinical
diagnosis or treatment of the patients.
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-32P]UTP,
[-32P]deoxy-CTP,
[125I]rT3, and
[125I]T4 were purchased
from NEN Life Science Products (Boston, MA). LH-20 was
obtained from Pharmacia Biotech (Uppsala, Sweden). AG
50W-X2 resin and protein assay kit were purchased from Bio-Rad Laboratories, Inc. (Hercules, CA). T7 RNA polymerase and SP6 RNA
polymerase were obtained from Nippon Gene (Tokyo, Japan). All other
chemicals at the highest quality were obtained from Sigma
(St. Louis, MO) or Wako Pure Chemical Industries, Ltd.
(Osaka, Japan) unless otherwise indicated.
Hormone measurements
Serum free T3 and free
T4 were measured by enzyme immunoassay using
Glaozyme [N] FT3-(S) and [N] FT4-(M) kits (SANYO Chemical
Industries, Kyoto, Japan), respectively. Serum TSH was measured by
two-site enzyme immunoassay using Glaozyme [New] TSH kit (SANYO
Chemical Industries). Sensitivities for free T3,
free T4, and TSH were 0.2 pg/ml, 0.04 ng/dl, and
0.014 µU/ml, respectively. Intra- and interassay coefficients of
variation were less than 4% and 8%, respectively, for each assay.
Tissue preparation
Thyroid tissues were obtained from tumor tissues and surrounding
nontumor tissues of the patients with hyperfunctioning thyroid adenoma
and papillary thyroid carcinoma at the time of surgery for the
measurement of deiodinase activity and RNA preparation. Thyroid tissues
were also obtained from the patients with Graves’ disease at the time
of subtotal thyroidectomy for the primary culture of thyroid cells.
Human thyroid cell culture
Thyroid tissues obtained from the patients with Graves’ disease
were dispersed by digestion with collagenase (CLS 2,Worthington Biochemical Corp., Freehold, NJ) and dispase (Life Technologies, Inc., Gaithersburg, MD) as previously described
(6, 7). Subsequently, thyroid cells were cultured in an
atmosphere of 5% CO2 and 95% air at 37 C in
Coon’s modified Ham’s F-12 medium supplemented with 5% calf serum,
penicillin (50 U/ml), streptomycin (50 U/ml), and a six-hormone mixture
containing bovine TSH (1 mU/ml), insulin (10 µg/ml), hydrocortisone
(5 nM), transferrin (5 µg/ml),
glycyl-L-histidyl-L-lysine-acetate (10 ng/ml),
and somatostatin (10 ng/ml). TSH is required to reorganize thyroid
cells into three-dimensional and functionally differentiated thyroid
follicles (8). After 24 h of culture, the medium was
replaced with a medium without TSH, and then the cells were cultured
for 3 days before the experiment.
Measurement of deiodinase activity
Thyroid microsomal fractions were obtained from tumor tissues or
surrounding nontumor tissues as previously described (4).
Briefly, thyroid tissues were homogenized in the homogenization buffer
(50 mM Tris-HCl and 0.25 M sucrose, pH 7.5,
containing 20 mM dithiothreitol and 1 mM EDTA).
Homogenates were centrifuged at 20,000 x g for 20 min
at 4 C, and the resultant supernatants were centrifuged at 200,000
x g for 90 min at 4 C to prepare microsomal fractions.
Microsomal pellets were resuspended in the homogenization buffer and
stored at -70 C. Cultured thyroid cells from each well were washed
twice with the washing buffer (100 mM potassium
phosphate, pH 7.0), scraped off, and transferred into 500 µl ice-cold
buffer (100 mM potassium phosphate, pH 7.0,
containing 20 mM dithiothreitol). After
centrifugation at 3,000 rpm for 15 min, the supernatants were
discarded. Pellets were sonicated in 100 µl sonication buffer (100
mM potassium phosphate, pH 7.0, containing 20
mM dithiothreitol and 1 mM
EDTA) per tube. Iodothyronine deiodinase activity was measured as
previously described (9). In brief, the samples were
incubated with 2 nM
[125I]T4, which was
purified using LH-20 column chromatography on the day of experiment, in
the incubation buffer (100 mM potassium
phosphate, pH 7.0, containing 20 mM
dithiothreitol, 1 mM EDTA, and 1
mM PTU) for 1 h at 37 C in duplicate. The
reaction was terminated by adding 100 µl 2% BSA and 800 µl 10%
trichloroacetic acid. After centrifugation at 3,000 rpm for 10 min, the
supernatant was applied to a small column packed with AG 50W-X2 resin
(bed volume, 1 ml) and eluted with 2 ml 10% glacial acetic acid.
Separated 125I was counted with a 
-counter.
Nonenzymatic deiodination was corrected by subtracting
I- released in tissue-free tubes. The protein
concentration was determined by Bradford’s method using BSA as a
standard (10). The deiodinating activity was calculated
either as the percentage of I- released or as
picomoles of I- released per mg protein/h after
multiplication by a factor of 2 to correct random labeling at the
equivalent 3' and 5' positions. In some experiments DII activity was
also measured by the difference between tracer iodide released at 2 and
100 nM T4; the latter
concentration was shown to saturate DII activity, but not DI activity
(4). Equimolar concentrations of I-
and T3 were produced by deiodination of
T4 as assessed by descending paper chromatography
(hexane-tertiary amyl alcohol-2 N ammonia), as
previously described (9).
RNA preparation and Northern analysis
Total RNA was isolated from thyroid tumor tissues, surrounding
nontumor tissues, or cultured thyroid cells from each well by the
modified acid guanidinium thiocyanate phenol-chloroform method
according to Chomczynski and Sacchi (11). Northern
analyses were performed as previously described (9). Human
DII cDNA fragment containing residues 110-1051 (3) and
human glyceraldehyde-3-phosphate dehydrogenase (G3PDH) cDNA fragment
containing residues 71–1053, which were cloned into pCRII
(Invitrogen, San Diego, CA), were used to synthesize
complementary RNA (cRNA) probes with
[-32P]UTP and SP6 RNA polymerase or T7 RNA
polymerase, respectively. Ten micrograms of total RNA per lane were
electrophoresed on a 1.4% agarose gel containing 2 M
formaldehyde and transferred overnight in 20 x SSC (1 x
SSC = 150 mM sodium chloride and 15 mM
trisodium citrate) to a nylon membrane (Biodyne, Pall BioSupport Corp.,
East Hills, NY). RNA was cross-linked to the nylon membrane with a UV
Stratalinker (Stratagene, La Jolla, CA). The membrane was
prehybridized with the hybridization buffer (50% formamide, 0.2% SDS,
5% dextran sulfate, 50 mM HEPES, 5 x SSC, 5 x
Denhart’s solution, and 250 µg/ml denatured salmon sperm DNA) at 68
C for 2 h. Subsequently, the membrane was hybridized at 68 C
overnight with the hybridization buffer containing a human DII cRNA
probe. The membrane was washed twice in 2 x SSC/0.1% SDS at 25 C
for 15 min and twice in 0.1 x SSC/0.1% SDS at 68 C for 1 h.
Autoradiography was established by exposing the filters for 6–24 h to
x-ray film (Kodak XAR-2, Eastman Kodak Co.,
Rochester, NY) at -70 C. After the detection of DII mRNA, the probe
was stripped off, and blots were rehybridized with human G3PDH cRNA
probe as a control. Hybridization and washing were performed as
described above, and the membrane was exposed for 1 h. mRNA levels
were quantitated by densitometry using NIH Image (version 1.61), and
the optical density of the DII band 7.5 kb in length was corrected for
G3PDH. RNA samples for comparison were analyzed on the same blot.
Isolation of genomic DNA of human DII and subcloning of the human
DII 5'-flanking region into the luciferase expression vector
Partial human DII cDNA (residues 110–1051) was labeled
with [-32P]deoxy-CTP by the random primer
method. The probe was used to screen a human placenta 
FIXII genomic
DNA library (Stratagene) and positive clones were
obtained. Sequencing analysis revealed that one of the clones was made
up of human DII cDNA residues 1–356, the preceding 12.8-kb 5'-flanking
region, and the subsequent 6.8-kb intron, as described previously
(12). To create the human DII promoter-luciferase
construct, the 832-, 784-, and 693-bp fragments immediately upstream of
the translation start site were generated by PCR using a human DII
genomic clone in Fix II (Stratagene) as a template.
Forward primers including the KpnI site
(underlined) were
5'-ATAGGTACCATCCTGGCCAAAGTAAAG-3' (832 bp),
5'-ATAGGTACCCCAAGATTAGGCTTTCACT-3' (784 bp), and
5'-ATAGGTACCACTTTGCACCACAGACAG-3' (693 bp), and the reverse
primer including a XhoI site (underlined) was
5'-ATACTCGAGCTTCTCTGCCTCCTGAGT-3'. The resulting single PCR
fragment was subcloned into the pGL3 basic luciferase expression vector
(Promega Corp., Madison, WI), between the XhoI
and KpnI sites. The identity and orientation of the PCR
fragment were then characterized by restriction enzyme analysis and DNA
sequencing. Large scale plasmid DNA purification was performed using
Maxiprep kit (QIAGEN, Valencia, CA).
Transient transfection and dual luciferase activity assay
The human DII promoter-luciferase constructs were transfected to
cultured human thyrocytes with Lipofectamine reagent (Life Technologies, Inc.), following the protocol provided by the
manufacturer. Each transfection was performed using 0.45 µg firefly
luciferase reporter construct DNA and 0.05 µg of an internal control
plasmid pRL-TK (which contains a herpes simplex virus thymidine kinase
promoter upstream of the Renilla luciferase gene;
Promega Corp.). Five hours after transfection, the
transfection medium was replaced by culture medium. Twenty-four hours
after transfection, where indicated, 1 mM
(Bu)2cAMP was added to the culture medium. After
24 h, the medium was removed, wells were rinsed with PBS, and then
the cells were lysed in passive lysis buffer (Promega Corp.) at room temperature for 30 min. Culture plates were
subjected to one cycle of freezing (-80 C) and thawing (room
temperature) to ensure complete cell lysis. The samples were
transferred to microcentrifuge tubes and then centrifuged at
12,000 x g for 30 sec at 4 C. Supernatants were used
for assay of luciferase activities. Firefly and Renilla
luciferase activities were sequentially measured using the Dual
Luciferase Reporter Assay System (Promega Corp.) according
to the manufacturer’s instructions. Firefly luciferase activities were
normalized based on the Renilla luciferase activity in each
well.
Statistics
All values are expressed as the mean ± SE.
Statistical differences were evaluated by ANOVA, followed by Dunnett’s
test using StatView 5.0 (Abacus Concepts, Inc., Berkeley, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, serum free thyroid hormones and serum TSH
were within the normal range in all patients with papillary thyroid
carcinoma. In contrast, serum free T3 was
increased, serum free T4 was within the normal
range, and serum TSH was undetectable in all patients with
hyperfunctioning thyroid adenoma.
DII activity and DII mRNA in thyroid tumor tissues and surrounding
nontumor tissues
Because not only DII, but also DI, is expressed in human thyroid
gland, it is important to distinguish those activities
(4). We have attempted to distinguish DII activities from
DI activities by two methods. First, T4
deiodinating activity was measured as the release of
I- from various concentrations of
T4 in the presence of 1 mM PTU in the
microsomal fraction of hyperfunctioning thyroid adenoma of case 2
(Table 1). As shown in Fig. 1, a double
reciprocal plot of deiodinating activity demonstrated that the
Km for T4 was 1.24
nM, and the maximum velocity (Vmax)
was 4.88 pmol/mg protein·h. A low Km of
T4 deiodinating activity is compatible with DII
activity. Km and Vmax are
comparable to those reported in the previous study using thyroid tissue
from a patient with Graves’ disease (4). The
Vmax of 4.88 pmol/mg protein·h is more than
5-fold that of human skeletal muscle, human placenta, or human
epidermal keratinocytes (5, 13). DII activity was then
measured as the release of I- from 2
nM T4 in the presence of 1
mM PTU in the microsomal fractions of tumor tissues and
surrounding nontumor tissues (Table 2).
Although DII activity was greater in the tissue of hyperfunctioning
thyroid adenoma than in surrounding nontumor tissue in each case, DII
activity was lower in the tissue of papillary thyroid carcinoma than in
surrounding nontumor tissue in each case. Thus, the DII activity ratio
(tumor tissue vs. nontumor tissue) was greater than 1 in
patients with hyperfunctioning thyroid adenoma and less than 1 in
patients with papillary thyroid carcinoma, as shown in Table 2. Because
it has been suggested that PTU is a poor inhibitor of DI at low
substrate levels, we also measured DII activity in some tissues as the
difference in fractional T4 deiodination between
low (2 nM) and high (100
nM) substrate levels; the latter concentration
has been shown to saturate DII activity, but not DI activity
(4). As the data shown in parentheses in Table 2 indicate, the results are in good agreement with those obtained by
the release of I- from 2
nM T4 in the presence of 1
mM PTU, and DII activities measured by two
different methods show a significant positive correlation (r =
0.983; P < 0.001). Figure 2 shows Northern analysis of DII mRNA in
tumor tissues and nontumor tissues from patients with hyperfunctioning
thyroid adenoma and papillary thyroid carcinoma. Although the results
of 24-h exposure are shown, a longer exposure clearly demonstrated the
DII mRNA with approximately 7.5 kb in all tumor tissues and nontumor
tissues. Although DII mRNA was greater in the tissue of
hyperfunctioning thyroid adenoma than in nontumor tissue in each case,
DII mRNA was lower in the tissue of papillary thyroid carcinoma than in
nontumor tissue in each case. Thus, the DII mRNA ratio (tumor tissue
vs. nontumor tissue) was greater than 1 in patients with
hyperfunctioning thyroid adenoma and less than 1 in patients with
papillary carcinoma, as shown in Fig. 3.
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, A and B. DII activity in cultured
thyroid cells was also significantly increased by TSH in a
dose-dependent manner as shown in Fig. 4B. These results indicate that
DII expression in the human thyroid gland is regulated by the TSH
receptor-mediated pathway.
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, a complete cAMP response element
(TGACGTCA) was observed -801 to -794 upstream of the translation
start site. Human DII promoter-luciferase constructs including the
832-, 784-, and 693-bp fragments upstream of the translation start site
were generated, as shown in Fig. 5B and transfected to cultured human
thyroid cells. The 832-bp construct including the cAMP response element
demonstrated stimulation by (Bu)2cAMP, whereas
other constructs lacking the cAMP response element were not stimulated
by (Bu)2cAMP, as shown in Fig. 5C. These results
indicate that the functional cAMP response element present in the
5'-flanking region of the human DII gene and human DII is
transcriptionally regulated by a cAMP-dependent mechanism in human
thyroid cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gene
(14), and constitutive activation of cAMP production has
been demonstrated in cultured cells from hyperfunctioning thyroid
adenoma that showed an activating mutation of
Gs compared with cells from surrounding
nontumor tissue in one of the cases analyzed in the present study
(6). The present results, therefore, strongly suggest that
DII activity and DII mRNA are increased as a result of constitutive
activation of the cAMP regulatory cascade in hyperfunctioning thyroid
adenoma. To avoid the variations in the results of DII expression among thyroid tissue samples because of possible difference in the procedure of surgery or the preparation of samples, we compared DII expression in tumor tissue and surrounding nontumor tissue in each case. Although it has been suggested that DII activity and DII mRNA are increased in hyperfunctioning thyroid adenoma (4), DII activity and DII mRNA in surrounding nontumor tissue of hyperfunctioning thyroid adenoma are not known. In the present study DII activity and DII mRNA were decreased in surrounding nontumor tissue compared with those in tissue from hyperfunctioning thyroid adenoma in each case. These results indicate that DII activity and DII mRNA are increased only in the tissue of hyperfunctioning thyroid adenoma and not in surrounding nontumor tissue. It is noteworthy that only serum free T3 was increased, and serum free T4 was within the normal range in all patients with hyperfunctioning thyroid adenoma, whereas serum free T3 and serum free T4 were within the normal range in all patients with papillary thyroid carcinoma in the present study. These results suggest that increased T3 production by DII in hyperfunctioning thyroid adenoma may contribute to elevated circulating T3 levels (4).
The present results demonstrated, for the first time, that DII activity and DII mRNA were decreased in the tissue from papillary thyroid carcinoma compared with surrounding nontumor tissue in each case. Therefore, there appears to be a striking difference in DII expression between hyperfunctioning thyroid adenoma and papillary thyroid carcinoma. The decrease in DII activity and DII mRNA in papillary thyroid carcinoma may be associated with dedifferentiation or malignant transformation of thyroid follicular cells.
We performed primary culture of human thyroid cells obtained from
patients with Graves’ disease to study the regulation of DII
expression in human thyroid gland. DII activity and DII mRNA were
detected in cultured human thyroid cells and were stimulated by TSH in
a dose-dependent manner. These results suggest that DII expression in
human thyroid cells is regulated by the TSH receptor-mediated
mechanism, which involves the cAMP regulatory cascade. Because serum
TSH is suppressed in patients with hyperfunctioning thyroid adenoma,
constitutive activation of the TSH receptor-cAMP regulatory cascade,
presumably due to an activating mutation in the TSH receptor gene or
the Gs gene, is responsible for the increased
expression of DII in hyperfunctioning thyroid adenoma tissue in the
present study. Analysis of the promoter region of human DII gene
revealed the presence of a complete cAMP response element (TGACGTCA)
-801 to -794 upstream of the translation start site of the gene. The
832-bp human DII promoter-luciferase construct including the cAMP
response element transfected to cultured human thyroid cells was
stimulated by (Bu)2cAMP, whereas other constructs
lacking the cAMP response element transfected to cultured human thyroid
cells were not stimulated by (Bu)2cAMP. These
results indicate that the functional cAMP response element is present
in the human DII gene, and human DII expression is transcriptionally
regulated by a cAMP-dependent mechanism in human thyroid cells.
Recently, cAMP-mediated mechanisms have been reported to be involved in
the pretranslational regulation of DII expression in human skeletal
muscle cells (9), rat astrocytes (15), and
rat pineal gland (16). In human skeletal muscle cells,
cAMP-stimulated DII expression was demonstrated to be suppressed by
thyroid hormones at both pretranslational and posttranslational levels
(9). It is, therefore, of considerable interest to
investigate the possible negative regulation of DII expression by
thyroid hormones in human thyroid gland in further studies. Recently,
the complete sequence of the human DII gene has appeared in GenBank
(AC007372), and Bartha et al. (17) demonstrated
the presence of functional cAMP response element in human DII promoter
using HEK-293 cells.
In conclusion, these results suggest that human thyroid DII expression
is regulated transcriptionally through the TSH receptor -subunit of
Gs protein-cAMP regulatory cascade, which may be
related to the increase in circulating T3 levels
in patients with Graves’ disease and hyperfunctioning thyroid
adenoma.
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Acknowledgments |
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Footnotes |
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Received February 13, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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s. Mol Cell Endocrinol 138:137–142[CrossRef][Medline]
q24.3 by in situ
hybridization. Cytogenet Cell Genet 84:73–74[CrossRef][Medline]
genes as a cause of toxic
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