Endocrinology Vol. 138, No. 2 602-606
Copyright © 1997 by The Endocrine Society
Thyroid-Stimulating Hormone-Induced Down-Regulation of Thyroid Transcription Factor 1 in Rat Thyroid FRTL-5 Cells
Tsukasa Saito,
Toyoshi Endo,
Minoru Nakazato,
Takahiko Kogai and
Toshimasa Onaya
Third Department of Internal Medicine, University of Yamanashi
Medical School, Tamaho, Yamanashi 409–38, Japan
Address all correspondence and requests for reprints to: Toshimasa Onaya, M.D., Third Department of Internal Medicine, University of Yamanashi Medical School, Tamaho, Yamanashi 409–38, Japan.
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Abstract
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Thyroid transcription factor 1 (TTF-1) is thought to play an important
role in the expression of genes that encode thyroid-specific proteins
such as thyroglobulin, thyroid peroxidase, and TSH receptor. The role
of TSH in the regulation of TTF-1 messenger RNA (mRNA) and protein
abundance was investigated in rat thyroid FRTL-5 cells. Northern blot
analysis revealed that TSH reduced TTF-1 mRNA abundance in a dose- and
time-dependent manner. Immunoblot analysis with rabbit antibodies
prepared against a recombinant fragment of TTF-1 expressed in bacteria
showed that TSH also reduced the amount of TTF-1 protein in FRTL-5
cells. Whereas the effect of TSH on TTF-1 mRNA was apparent after
3 h, the effect on TTF-1 protein was not apparent until 12 h
after TSH addition to the cells. Both TTF-1 mRNA and protein were
significantly decreased after the addition of (Bu)2 cAMP or
forskolin for 24 h, whereas they were not decreased by
12-O-tetradecanoyl-phorbol-13-acetate. These results indicate that TSH
down-regulates TTF-1 expression in FRTL-5 cells via the cAMP pathway.
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Introduction
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HOMEODOMAIN-CONTAINING proteins,
which contribute to the regulation of morphogenesis in
Drosophila, bind to specific DNA sequences and exert their
effects through modulation of transcription (1, 2). Thyroid
transcription factor 1 (TTF-1), a homeodomain-containing
thyroid-specific transcription factor (3) that is related to the
Drosophila NK2 family of homeobox-containing proteins (4),
is thought to be important for thyroid development and differentiation
(5). Thus, TTF-1 is required for the expression of various
thyroid-specific genes, including those encoding thyroglobulin (Tg),
thyroid peroxidase (TPO), and the TSH receptor (TSHR) (6, 7, 8, 9). TTF-1
binds to 5' flanking region of TSHR gene and stimulates the
transcriptional activity, whereas TSH reduces the abundance of TTF-1
messenger RNA (mRNA). Therefore, the down-regulation of TTF-1 by TSH
seems to contribute to the negative regulation of TSHR in the thyroid
(9). TSH activates both the cAMP and phosphatidylinositol cascades in
thyroid cells (10). Both or either of these two regulatory cascades
could be involved in TTF-1 gene activation and protein expression.
However, TSH has not been shown directly to reduce the amount of TTF-1
protein in thyroid cells, although the signal corresponding to the
TTF-1-DNA complex in a gel mobility shift assay was decreased after
treatment of cells with forskolin (9).
We now have produced rabbit antibodies to TTF-1 with a portion of TTF-1
protein expressed in bacteria as antigen and, with the use of
immunoblot analysis with these antibodies, have investigated the effect
of TSH on TTF-1 protein expression in rat thyroid FRTL-5 cells.
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Materials and Methods
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Cell culture
Rat thyroid FRTL-5 cells were cultured in 10-cm dishes
containing Coon’s modified Ham’s F12 medium supplemented with 5%
calf serum (GIBCO, Grand Island, NY) and a 6-hormone mixture containing
bovine TSH (5 mU/ml), insulin (10 µg/ml), 10 nM
hydrocortisone, transferrin (5 µg/ml), SRIF (10 ng/ml), and
glycyl-L-histidyl-L-lysine acetate (10 ng/ml)
as described previously (11, 12). After achieving 70–80% confluence,
the cells were maintained in the same medium without TSH and cultured
for an additional 5 days. Cells then were subjected to the experiments.
BRL-3A rat liver cells were cultured in 10-cm dishes containing Coon’s
modified Ham’s F12 medium supplemented with 5% FBS without the 6
hormones.
Northern blot analysis
Total RNA was isolated from cells with acidic guanidine
isothiocyanate-phenol-chloroform extraction (13), fractionated (15 µg
per lane) by electrophoresis through 1% agarose gels, and transferred
to nylon filters (Zeta Probe, Bio-Rad, Richmond, CA). The filters were
hybridized with a 32P-labeled probe corresponding to
nucleotides +1 to +331 (relative to the translation start site) of
TTF-1 complementary DNA (cDNA) or rat ß-actin cDNA and then washed as
previously described (12). Signals corresponding to TTF-1 mRNA were
quantitated with a BAS 2000 system (Fujix, Tokyo, Japan).
Preparation of TTF-1 antibodies
A recombinant partial TTF-1 residue, corresponding to 1 to 126,
expressed in bacteria with pGEX-2T (Pharmacia Biotech, Uppsala,
Sweden) was purified using Glutathione Sepharose 4B (Pharmacia).
Antisera were raised in rabbits by serial injections of emulsion of the
protein (1 mg/ml) in Freunt’s complete adjuvant (Wako, Osaka, Japan),
and after 10 weeks, the sera were used in the experiments.
Gel mobility shift assay
Nuclear extracts from FRTL-5 and BRL-3A cells were prepared as
described previously (14, 15). A synthetic double-stranded
oligonucleotide probe spanning nucleotides -194 to -169 of the TSHR
gene promoter, which contains the TTF-1-binding site, was labeled with
[
-32P]ATP (9). Nuclear extracts (1.5 µg protein)
were incubated for 20 min at room temperature in a reaction vol of 20
µl containing 10 mM Tris HCl (pH 7.6), 50 mM
KCl, 1 mM EDTA, 5 mM MgCl2, 12.5%
(vol/vol) glycerol, 1 mM dithiothreitol, 0.1% Nonidet
P-40, and 1 µg poly(dI-dC), either in the absence or presence of
rabbit antiserum (1:200 dilution) to recombinant TTF-1 residues 1 to
126 or preimmune serum (1:200 dilution). Labeled probe (6000 cpm, 0.5
ng), with or without unlabeled competitor oligonucleotide (25 or 100
ng), was then added to the reaction mixture, and the incubation was
continued for an additional 20 min. DNA-protein complexes were
separated on 8% native polyacrylamide gels (9).
Immunoblot analysis
Nuclear extracts (15 µg protein per lane) from FRTL-5, BRL-3A,
or COS-7 cells that had been transfected with the pRc/CMV vector
containing the full coding sequence of rat TTF-1 cDNA (kindly provided
by Dr. R. Di Lauro) were mixed with lysis buffer [62.5 mM
Tris-HCl (pH 6.8), 9.5 M urea, 2.3% SDS, 10% glycerol,
and 5% ß-mercaptoethanol], subjected to electrophoresis on 15%
polyacrylamide gels containing 0.1% SDS, and transferred to a
nitrocellulose membrane. The membrane was then incubated sequentially
with rabbit antiserum to TTF-1, peroxidase-conjugated goat antibodies
to rabbit IgG, and diaminobenzidine (Dojindo, Kumamoto, Japan) as
previously described (12). The protein abundance was quantitated by
scanning densitometer (GT-8000, EPSON, Tokyo, Japan).
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Results
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Northern blot analysis of TTF-1 mRNA
First, we determined TTF-1 mRNA signal in FRTL-5 cells, and the
strong signal was seen in the position of approximately 2.7 kb as
reported in the previous study (3). To investigate the effect of TSH on
the TTF-1 mRNA amount, the following experiments were performed.
Northern blot analysis revealed abundant TTF-1 mRNA in untreated FRTL-5
cells and that incubation of cells with TSH (5 mU/ml) for 3 or 24
h reduced the amount of this mRNA (Fig. 1A
). TTF-1 mRNA
was not detected in BRL-3A cells. The TSH-induced decrease in the
amount of TTF-1 mRNA in FRTL-5 cells was dose dependent for
concentration of > 1 mU/ml (Fig. 1B). Figure 2
shows time-dependent TSH effect on the amount of TTF-1 mRNA in FRTL-5
cells. It was reduced by 50 and 66% after incubation with TSH (5
mU/ml) for 3 and 24 h, respectively; exposure to TSH for 1 h
did not affect transcript abundance. TTF-1 mRNA amount was reduced
rapidly during a few hours.
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Figure 1. A, Effect of TSH on the abundance of TTF-1 mRNA in
FRTL-5 cells. FRTL-5 cells were maintained for 5 days in the absence of
TSH and then exposed to TSH (5 mU/ml) for 0 h (lane a), 3 h
(lane b), or 24 h (lane c). Total RNA was isolated from the cells
and subjected to Northern analysis with a TTF-1 cDNA probe. Total RNA
from BRL-3A cells also was analyzed (lane d). The lower
panel shows the Northern analysis of the same blot with a rat
ß-actin cDNA probe. B, Northern blot analysis of the effect of TSH
concentration on TTF-1 mRNA abundance in FRTL-5 cells. Cells were
maintained for 5 days in the absence of TSH and then incubated for
24 h in the absence (lane a) or presence of TSH at 0.01, 0.1, 1,
5, 10 mU/ml (lanes b to f, respectively). The lower panel shows the
Northern analysis of the same blot with a rat ß-actin cDNA probe.
Data in (A) and (B) represent typical experiments that were repeated
three times with different batches of cells on different days.
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Figure 2. Time course of the effect of TSH on TTF-1 mRNA
abundance in FRTL-5 cells. Cells were maintained for 5 days without TSH
and then incubated with TSH (5 mU/ml) for the indicated times. Total
RNA was prepared from the cells and subjected to Northern analysis with
TTF-1 and ß-actin cDNA probes. After quantitative densitometry, the
TTF-1/actin ratio was calculated and compared with the zero time
control. Data are means ± SE of four separate
experiments with different batches of cells on different days and are
expressed relative to the zero time control. a, P
< 0.01 vs. zero time control (Student’s
t test).
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Production and characterization of antiserum to TTF-1
We produced a rabbit antiserum to TTF-1 by immunization with a
recombinant fragment of TTF-1 expressed in bacteria. To confirm the
specificity of the antiserum, a gel mobility shift analysis was
performed using a TTF-1-binding site located in the 5' flanking region
of the TSHR gene. Figure 3A shows the gel mobility shift
analysis with nuclear extract from FRTL-5 cells, in which TTF-1
migrated in the position of the lower arrow; competing
unlabeled oligonucleotide reduced the radioactivity at this position in
a dose-dependent manner (lanes a to c). Antiserum to TTF-1 induced a
shift in the position of the labeled band to that indicated by the
upper arrow, whereas preimmune serum did not, suggesting the
specific binding of the antiserum to TTF-1 protein. Nuclear extract
from BRL-3A cells did not yield a TTF-1 band. The band below TTF-1 from
FRTL-5 cells seems to correspond to a single-stranded DNA-binding
protein described previously (9, 13).
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Figure 3. A, Effect of antiserum to TTF-1 on TTF-1 mobility
in a gel mobility shift assay. Nuclear extract from FRTL-5 cells that
had been cultured in the absence of TSH for 5 days was incubated in the
absence or presence of antiserum to TTF-1 (1:200 dilution); a, no
serum, no competitor; b, no serum, 25 ng competitor; c, no serum, 100
ng competitor; d, antiserum (x 200), no competitor; and e, preimmune
serum (1:200 dilution), no competitor oligonucleotide as indicated
(lanes a to e). Nuclear extract from BRL-3A cells also was analyzed
(lane f). A synthetic oligonucleotide spanning nucleotides -194 to
-169 of the TSHR gene promoter was used as the 32P-labeled
probe and unlabeled competitor. The lower and upper
arrows indicate the positions of TTF-1 protein in the absence
or presence of specific antiserum, respectively. The signal below the
lower arrow corresponds to a single-stranded DNA-binding
protein. B, Immunoblot analysis of TTF-1 protein. Nuclear extracts from
COS-7 cells transfected with the pRc/CMV vector containing the full
coding sequence of TTF-1 cDNA (lanes a and c) and BRL-3A cells (lane b)
were subjected to immunoblot analysis with rabbit antiserum to TTF-1
(1:1000 dilution) (lanes a and b) or preimmune serum (1:1000 dilution)
(lane c). The arrow indicates the position of TTF-1
protein (46 kDa). Molecular size (kilodaltons) is indicated to the
left. Data represent typical experiments that repeated three
times with different batches of cells on different days.
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We also confirmed the specificity of the antiserum to TTF-1 by
immunoblot analysis. The antiserum detected TTF-1 (46 kDa) in the
nuclear extract of COS-7 cells transfected with TTF-1 cDNA in the
pRc/CMV vector but not in the nuclear extract of BRL-3A cells (Fig. 3B
). Preimmune serum did not detect TTF-1 in the nuclear extract of the
transfected cells.
Effect of TSH on TTF-1 protein
To further elucidate the down-regulation of TTF-1 by TSH, nuclear
extracts prepared from FRTL-5 cells that had been incubated with TSH
for various times were subjected to immunoblot analysis with the
antiserum to TTF-1. A decrease in the amount of TTF-1 protein (46 kDa)
was first detected after incubation of cells with TSH for 12 h and
was still apparent after 24 h (Fig. 4A). In
contrast, Northern blot analysis of total RNA from the same batch of
cells showed that TTF-1 mRNA abundance was decreased after incubation
of cells with TSH for 3 h (Fig. 4B).
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Figure 4. A, Effect of TSH on TTF-1 protein expression.
FRTL-5 cells were maintained in the absence of TSH for 5 days and then
incubated with TSH (5 mU/ml) for 0, 3, 6, 12, 24 h. Nuclear
extracts were prepared and subjected to immunoblot analysis with
antiserum to TTF-1. Data are means ± SE of four
separate experiments with different batches of cells on different days
and are expressed relative to zero time control. *,
P < 0.01 vs. 0, 3, 6 h
(Student’s t test). B, Effect of TSH on TTF-1 protein
and mRNA. FRTL-5 cells were maintained in the absence of TSH for 5 days
and then incubated with TSH (5 mU/ml) for 0, 3, 6, 12, 24 h (lanes
a–e). Nuclear extracts were prepared and subjected to immunoblot
analysis with antiserum to TTF-1. Total RNA was prepared from the cells
and subjected to Northern analysis with a TTF-1 cDNA or a rat ß-actin
cDNA probe. Data represent typical experiments that were repeated four
times with different batches of cells on different days.
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Effect of (Bu)2 cAMP, forskolin, and
12-O-tetradecanoyl-phorbol-13-acetate (TPA)
To clarify a possible mechanism of action of TSH in the regulation
of TTF-1 expression, (Bu)2 cAMP, forskolin, or TPA was
added to the cells, and the levels of TTF-1 mRNA and protein were
determined. Figure 5 shows that both TTF-1 mRNA and
protein were significantly decreased after the addition of
(Bu)2 cAMP (1 mM) or forskolin (10
µM) for 24 h, whereas TPA (200 nM) had
no effect on the abundance of the mRNA and protein.
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Figure 5. A, Effect of (Du)2cAMP, forskolin, and
TPA on TTF-1 mRNA and protein. FRTL-5 cells were maintained in the
absence of TSH for 5 days and then incubated with: a, none; b, TSH (5
mU/ml); c, (Bu)2 cAMP; d, forskolin (10 µM);
e, TPA (200 nM). Total RNA and nuclear extract were
prepared and subjected to Northern and immunoblot analyses,
respectively. The representative data are shown. B, Effect of
(Bu)2cAMP, forskolin, and TPA on TTF-1 mRNA and protein.
Samples were prepared as described in (A). Data are means ±
SE of three (Northern analysis) or four (immunoblot
analysis) separate experiments with different batches of cells on
different days and are expressed relative to none (a). *,
P < 0.005; **, P < 0.05
vs. none and TPA (Student’s t test).
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Discussion
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The rat TTF-1 cDNA encodes a 378-amino acid protein with a
calculated molecular mass of 38 kDa (3). Purified TTF-1 from HeLa
spinner cells infected with a vaccinia virus containing the entire
TTF-1 open reading frame was previously shown to migrate on SDS-PAGE
with an apparent molecular mass of 38 kDa (16). We now have shown that
antibodies prepared against residues 1–126 of TTF-1 detect a portion
of 46 kDa. This discrepancy in molecular size might be attributable to
posttranslational modification such as phosphorylation, glycosylation,
or proteolysis. Van Renterghem et al. (17) reported that
the molecular size of TTF-1 was approximately 43–46 kDa in
immunoprecipitation and immunoblotting with anti-TTF-1 antibody. This
is compatible with our results. Indeed, TTF-1 possesses several
phosphorylation sites that might be important determinants of
DNA-binding activity (9) and also possesses several glycosylation
sites. There were two faint bands just above and beneath the 46-kDa
TTF-1 protein in our immunoblot analysis. The possibility that these
immunodetected signals might be phosphrylated or dephosphorylated forms
of TTF-1 protein can not be disregarded. Although TTF-1 can exist as a
dimer as a result of disulfide bond formation between two cysteine
residues located outside the homeodomain (16), we performed
electrophoresis under reducing conditions.
Our observation of TSH-induced down-regulation of TTF-1 mRNA is
consistent with the results of a previous study (9). We now have
demonstrated also that TSH reduces the amount of TTF-1 protein in
FRTL-5 cells (Fig. 4); this effect was first apparent after 12 h,
whereas mRNA down-regulation was detected after incubation of cells
with TSH for 3 h. Recently, Zannini et al. (18) showed
that the amount of 35S-labeled TTF-1 decreased by 50% in
about 14 h in FRTL-5 cells and transfected HeLa cells, suggesting
the slow turnover of this protein and also supporting our result. Van
Renterghem et al. (17) showed that TTF-1 mRNA abundance was
not affected by incubation of primary cultures of dog thyroid
with forskolin for 3 days. This apparent discrepancy with our data may
be attributed to the difference in primary vs. continuous
cell line, FRTL-5. However, it is also possible that species-specific
differences exist in TTF-1 gene regulation.
A similar discrepancy in mRNA regulation is apparent also with another
thyroid-specific gene, that for TSHR. Saji et al. (19)
showed that TSHR mRNA was down-regulated by the TSH-cAMP pathway in
FRTL-5 cells, whereas others (20, 21) demonstrated TSH-induced
up-regulation of TSHR mRNA in primary cultures of human and dog thyroid
cells. As a cAMP response element (CRE)-like region and a TTF-1-binding
site in the 5' flanking region of the TSHR gene contribute to the
regulation of transcription of this gene (8, 9), this difference in the
regulation of TSHR gene by TSH may reflect that of the TTF-1 gene by
TSH.
The regulation of the expression of Tg, TPO, and TSHR genes has been
elucidated by analysis of their 5' flanking sequences (6, 7, 8, 9, 22, 23).
It was demonstrated that the cAMP pathway had an important role in the
down-regulation of TTF-1 mRNA and protein by TSH (Fig. 5). Although
there is unexpectedly no CRE (CREB/CREM consensus sequence) within 2.5
kb of the 5'-upstream region of TTF-1 gene (Ref. 24 and unpublished
observations), a candidate for the consensus sequence of cAMP receptor
protein is located there (25, 26). Our recent characterization of the
5'-flanking region of TTF-1 gene may therefore help to elucidate the
mechanism of not only TTF-1 gene regulation by TSH, but also Tg, TPO,
and TSHR gene regulation (24).
Received May 24, 1996.
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A. Losada, J. A. Tovar, H. M. Xia, J. A. Diez-Pardo, and P. Santisteban
Down-Regulation of Thyroid Transcription Factor-1 Gene Expression in Fetal Lung Hypoplasia Is Restored by Glucocorticoids
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M. Ohmori, N. Harii, T. Endo, and T. Onaya
Tumor Necrosis Factor-{alpha} Regulation of Thyroid Transcription Factor-1 and Pax-8 in Rat Thyroid FRTL-5 Cells
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[Abstract]
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L. Perrone, G. Tell, and R. Di Lauro
Calreticulin Enhances the Transcriptional Activity of Thyroid Transcription Factor-1 by Binding to Its Homeodomain
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Autoregulation of thyroid-specific gene transcription by thyroglobulin
PNAS,
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[Abstract]
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T. Endo, M. Kaneshige, M. Nakazato, M. Ohmori, N. Harii, and T. Onaya
Thyroid Transcription Factor-1 Activates the Promoter Activity of Rat Thyroid Na+/I- Symporter Gene
Mol. Endocrinol.,
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[Abstract]
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A. S. Kumar, V. C. Venkatesh, B. C. Planer, S. I. Feinstein, and P. L. Ballard
Phorbol Ester Down-regulation of Lung Surfactant Protein B Gene Expression by Cytoplasmic Trapping of Thyroid Transcription Factor-1 and Hepatocyte Nuclear Factor 3
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Top
Abstract
Introduction
