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Third Department of Internal Medicine, Yamanashi Medical University, Yamanashi 409–38, Japan
Address all correspondence and requests for reprints to: Dr. T. Onaya, Third Department of Internal Medicine, Yamanashi Medical University, Tamaho, Yamanashi 409–38, Japan. E-mail: onayat{at}res.yamanashi-med.ac.jp
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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27 times basal (5H medium) levels] at 72
h. In contrast, Northern blot analysis, using rat NIS complementary DNA
as a probe, revealed that addition of TSH to these cells significantly
increased NIS mRNA at 3–6 h, reaching a maximum after 24 h
(5.9 times basal levels). Forskolin and (Bu)2cAMP
mimicked this stimulatory effect on both the I-
transport activity and mRNA levels.
D-ribofranosylbenzimidazole, a transcription inhibitor,
almost completely blocked TSH-induced stimulation of
I- transport and NIS mRNA levels. Western blot
analysis demonstrated that TSH increased NIS protein levels at 36
h, reaching a maximum at 72 h, in parallel with the kinetics of
TSH-induced I- transport activity. However, it
also showed that the amount of NIS protein already present in FRTL-5
cell membranes before the addition of TSH was about one third of the
maximum level induced by TSH. These results indicate that stimulation
of I- transport activity by TSH in thyrocytes is
partly due to a rapid increase in NIS gene expression, followed by a
relatively slow NIS protein synthesis. However, the existence of an
abundant amount of protein in quiescent FRTL-5 cells with very low
I- transport activity also suggests that this
activity is controlled by another TSH-regulated factor(s). |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Using FRTL-5 cells (7), a cultured rat thyroid follicular cell line, Weiss et al. found that TSH stimulates I- transport through cAMP signaling, and that this stimulation depends on cycloheximide-sensitive de novo protein synthesis (6). They also found that 12–24 h were needed for the onset of stimulation of I- transport by TSH.
Kaminsky et al. (8) demonstrated that membrane vesicles from TSH-deprived FRTL-5 cells have I--accumulating activity similar to that of vesicles from TSH-stimulated cells. From these observations, they proposed that iodide transporter molecules are present in the cell membrane even in the absence of TSH, and that TSH stimulates I- uptake via another unknown factor(s).
Recently, Dai et al. (9) succeeded in cloning rat NIS complementary DNA (cDNA) and revealed that it encodes an intrinsic membrane protein with 12 putative transmembrane domains. Their results opened the way to analyze the mechanism of iodide transport activation by TSH at the molecular level.
To determine whether TSH stimulates NIS gene expression and then increases the amount of NIS protein itself, we studied the effects of TSH on NIS messenger RNA (mRNA) and protein levels in FRTL-5 cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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When the cells reached 70–80% confluence, the medium was replaced, and the cells were washed twice with Hanks’ Balanced Salt Solution (HBSS) and then maintained in 5H medium (no TSH) or another medium for 8 days before use in individual experiments. It has been reported that the cells can be maintained in culture medium without TSH for at least 10 days and still remain viable (10).
Chinese hamster ovary cells (CHO-K1 cells), which were used as a negative control in Western blot analysis, were grown in 100-mm dishes in Coon’s modified Ham’s F-12 medium supplemented with 10% calf serum.
Measurement of
125I- uptake by FRTL-5
cells
Uptake of 125I- by FRTL-5 cells
was measured as previously described (11). Briefly, the cells were
washed twice with 1 ml modified HBSS (137 mM NaCl, 5.4
mM KCl, 1.3 mM CaCl2, 0.4
mM MgSO4, 0.5 mM MgCl2,
0.4 mM Na2HPO4, 0.44 mM
KH2PO4, and 5.55 mM glucose with 10
mM HEPES buffer, pH 7.3) and incubated for 40 min at 37 C
in 200 µl modified HBSS containing about 0.02 µCi carrier-free
Na125I and 1.0 µM NaI, with a final specific
activity of 10–20 mCi/mmol. When incubations were terminated, the
cells were washed twice with ice-cold HBSS. Four hundred microliters of
95% ethanol were added to each well for 30 min, half of the well
contents were then transferred into vials for counting with a
-counter. I- uptake was expressed as picomoles per µg
DNA. The DNA content was determined for each well using the material
not extracted with ethanol according to the method of Kissane et
al. (12).
Measurement of iodide efflux
Iodide efflux was measured by the methods of Weiss et
al. (11, 13) with minor modifications. FRTL-5 cells grown in 35-mm
diameter dishes were incubated for 40 min at 37 C with 2 ml HEPES (10
mmol/liter)-buffered HBSS containing about 0.1 µCi carrier-free
Na125I/ml and 1 µmol NaI/liter. At the end of the
incubation, the medium was carefully removed and replaced every 2 min
with 2 ml fresh nonradioactive buffered HBSS containing 1
µM NaI. After the last medium was removed, the cells were
extracted with ethanol for counting, along with the previously
collected medium samples.
Efflux data are presented as the rate coefficients based on the counts per min remaining (as a percentage of the total) at the indicated times and were calculated as described by Weiss et al. (11, 13).
Probe for detecting
Na+/I- symporter
mRNA
We prepared the NIS cDNA as previously described (14). Briefly,
total RNA from rat thyroid gland was prepared by guanidine thiocyanate
extraction and CsCl centrifugation (15), and mRNA was isolated using
oligo(deoxythymidine)-Latex. For PCRs, mRNA was transcribed into cDNA
with avian reverse transcriptase and then used as a template. The PCR
primers used to obtain NIS cDNA were as follows [the A in the ATG
initiation codon of rat NIS cDNA (8) is designated +1]: sense primer,
nucleotide (nt) -29 to -9; and antisense primer, nt 1955 to 1975. PCR
was performed for 30 cycles as follows: 0.5 min at 94 C, 1 min at 55 C,
and 2 min at 74 C. NIS cDNA (extending from nt -29 to 1975) and rat
ß-actin cDNA inserts were labeled with
[
-32P]deoxy-CTP using a random primer labeling
kit (Takara Shuzo, Tokyo, Japan).
Northern blot analysis
Total RNA from FRTL-5 cells was isolated by guanidine
thiocyanate extraction and CsCl centrifugation (15). Total RNA (20
µg/lane) was electrophoresed on 1.2% agarose and transferred to
cellulose acetate membranes (Zeta-Probe, Bio-Rad Laboratories,
Richmond, CA). For normalization in the NIS mRNA stability examination,
the electrophoresed 28S ribosomal RNA that was stained by ethidium
bromide was quantified by densitometry. Blots were prehybridized
overnight at 42 C in 50% formamide, 10 x Denhardt’s solution
(0.2% Ficoll, 0.2% polyvinilpyrolidone, and 0.2% BSA), 5 x
SSPE (20 x SSPE = 3 M NaCl, 0.2 M
sodium phosphate, and 20 mM EDTA, pH 7.4), 0.1% SDS, 0.1
mg/ml heat-denatured salmon sperm DNA, and 1.0 µg/ml polyadenylase.
Hybridization was performed at 42 C for 12 h with the radiolabeled
probe in fresh hybridization solution. Filters were washed three times
at room temperature in 2 x SSC (20 x SSC is 3 M
NaCl and 0.3 M sodium acetate, pH 7.0) containing 0.1%
SDS. Stringent washes were performed three times for 30 min each time
at 55 C in 0.1 x SSC-0.1% SDS. An imaging plate was exposed to
the filters for 2 h, and the results were analyzed with a Bas 2000
Image Analyzer (Fuji Film Co., Tokyo, Japan).
Western blot analysis
We prepared anti-NIS protein antibody as previously described
(14, 16). Briefly, rat NIS cDNA obtained by PCR was ligated into
pGEX-2T, and the glutathione-S-transferase (GST)/N-terminal
portion of NIS (amino acids 1–231) fusion protein was purified. Serum
from rabbits immunized with the fusion protein was shown to contain
anti-NIS antibodies (14).
FRTL-5 cells or CHO-K1 cells were collected and resuspended in 5 vol homogenizing buffer \[10 mM Tris-HCl (pH 7.4), 5 mM NaCl, 1 mM EDTA, 0.1 mM phenylmethylsulfonylfluoride, and 50 µg/ml leupeptin\] containing 0.25 M sucrose. After gentle homogenization at 4 C, the lysates were centrifuged at 700 x g for 10 min at 4 C. The supernatants were further centrifuged at 100,000 x g for 90 min at 4 C to obtain the total postnuclear membrane fraction. The membranes were resuspended in the homogenizing buffer at a protein concentration of 1 mg/ml and kept at -80 C. The lysates (exactly 20 µg protein/lane) were added to the same volume of sample buffer (10% glycerol, 2% SDS, and 0.0625 M Tris-HCl, pH 6.8) and heated without 2-mercaptoethanol at 90 C. These were subjected to 0.1% SDS-10% PAGE. Electrotransfer to nitrocellulose membranes was performed. The blots were stained according to the method of Hawkes et al. (17). Briefly, after blocking with 5% low fat milk, blots were exposed to anti-NIS/GST fusion protein antibody (1:500) at 4 C for 12 h. Peroxidase-conjugated goat antirabbit IgG was added at a 1:1000 dilution for 1 h at room temperature. The binding of rabbit antisera to NIS was quantified by reflection densitometry. We had preliminarily confirmed that the quantitation of binding to the NIS protein was linear for the applied protein quantity of the membrane fraction (data not shown).
Protein measurements
Protein was measured using the Coomassie blue dye method
(Bio-Rad protein assay, Bio-Rad Laboratories, Richmond, CA) with BSA as
standard.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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When FRTL-5 cells were precultured in the absence of TSH for 8 days and
then exposed to 6H medium (containing 1 mU/ml TSH), I-
uptake by FRTL-5 cells increased after a latency period of 24 h,
reaching a maximum [27.5 times basal (0 h) levels; 1.15 times
the level before deprivation of TSH; data not shown] after 72 h
(Fig. 1
).
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, inset); the
efflux had no significant effect on the increase in I-
uptake after TSH stimulation.
Northern blot analysis revealed a major mRNA species of 2.9 kilobases
(Figs. 2, 3, and 5) and, in some cases, closely related
minor faint bands (Figs. 2 and 3). The former is similar in size to
that found in a recent report (8). As the minor bands are not able to
be detected in Fig. 5, it is likely that these faint bands are the
degradation products of the message. Time-course studies revealed that
NIS mRNA levels were markedly increased after 6 h of stimulation,
reaching a maximum (6.2 times basal levels) after 24 h and
slowly declining to about 4.4 times basal levels after 72 h (Fig. 2).
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1.7 times control levels), and
maximum stimulation was observed at 1.0 mU/ml, but the higher
concentration of TSH increased NIS mRNA levels to a lesser extent (Fig. 3).
To assess the role of mRNA stability in the observed changes in NIS
mRNA, RNA synthesis was blocked with 40 µM
D-ribofranosylbenzimidazole before or 12 h after the
addition of TSH, and the relative rates of disappearance of NIS mRNA
were determined by Northern blot analysis (Fig. 4).
Although NIS message levels are low in quiescent cells, long exposure
of the blots to the imaging plate made it possible to obtain enough
signals. We estimated the half-lives of NIS mRNA in TSH-deprived FRTL-5
cells and TSH-stimulated cells to both be approximately 7.2 h; TSH
had no significant effect on the rate of disappearance of NIS mRNA
during the first 6 h after exposure.
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).
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10.3-fold over control levels) and NIS mRNA (3.9-fold over basal
levels; Fig. 5 and Table 2).
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).
Effects of TSH on
Na+/I- symporter
protein levels
As described above, NIS mRNA levels reached a maximum 24 h
after TSH stimulation, although I- uptake reached a
maximum at 72 h. To investigate whether this lag resulted from
translational events, we performed Western blot analysis.
As described previously (14, 16), we produced the anti-GST/NIS fusion
protein antibodies, which recognized an 80-kDa protein in FRTL-5 cell
membranes, the size of which agrees well with that reported for NIS by
Carrasco et al. (personal communication). As reported above,
this 80-kDa positive staining was absorbed by the addition of the
fusion protein, but the smaller Mr faint bands observed in
Fig. 6 were not. Preimmune serum also did not stain
80-kDa protein, but weakly bound the latter bands (14), suggesting that
several faint bands below 65 kDa in Fig. 5 were nonspecific staining.
Using the anti-NIS antibody, we could not observe 80-kDa protein in the
membrane fraction from nonthyroid cells, CHO-K1 cells (Fig. 6C).
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2.6-fold over basal (5H) levels; about the same level as before
the deprivation of TSH] after 72 h of stimulation (Fig. 6B). To determine whether the effect of cycloheximide on iodide accumulation was due to the decrease in NIS protein, we performed Western blot analysis using FRTL-5 cells maintained with 1 mU/ml TSH and 10 µg/ml cycloheximide for 48 h. The addition of cycloheximide decreased NIS protein by about 0.6-fold the 6H (stimulated by TSH for 48 h) levels.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As I- uptake by thyrocytes is influenced by various factors, the reasons for this lag has been actively debated (2, 6, 8, 18). One possibility may involve redistribution of NIS molecules to the plasma membrane. Exposure to TSH might trigger a redistribution of NIS molecules to the plasma membrane in an exocytosis-like fashion similar to the effect of insulin-induced transfer of glucose transporter molecules to the plasma membrane (19, 20, 21, 22, 23). However, this effect of insulin is observed within 10 min of exposure, making it difficult to explain the effect of TSH on NIS molecules by analogy to the action of insulin on glucose transporters.
Recently, Kaminsky et al. reported interesting data showing that membrane vesicles prepared from FRTL-5 cells cultured in the absence of TSH are able to accumulate iodide at the same rate as those from cells cultured in the presence of TSH (8). As the NIS activity of quiescent FRTL-5 cells is very low, they speculated that NIS molecules are present even in the absence of TSH, and that TSH may activate NIS through some modulator(s) (8).
However, our Northern blot analysis clearly demonstrates that TSH increased NIS mRNA itself in less than 6 h. Because TSH did not affect the degradation rate of NIS mRNA, TSH stimulated NIS gene transcription. Further, immunodetection of NIS protein by anti-NIS antibody demonstrated that TSH increased the amount of protein 12–24 h after the increase in mRNA. Despite the increase in protein, this does not directly mean that NIS protein synthesis is stimulated by TSH. To clarify this, further elucidation, such as a pulse-chase experiment and the study of the protein stability, will be needed. However, as the present data indicate that the marked increase in NIS mRNA is followed by the increase in protein, we presume that TSH increased NIS protein via a transcriptional mechanism.
On the other hand, despite the small amount of message, our Western blot analysis indicated that quiescent FRTL-5 cells contained about one third the amount of NIS protein found in maximally induced cells. The reason for this discrepancy remains obscure, but long exposure of the filter to the imaging plate made it possible to detect a weak signal of NIS message. Therefore, we presumed that NIS protein may be produced to a certain extent even in the absence of TSH. These data agree with the results of Kaminsky et al. (8) with regard to the presence of NIS protein in TSH-deprived cells.
In addition to the existence of NIS protein in the absence of TSH, it is of particular interest that iodide uptake is increased about 27-fold by TSH, whereas NIS protein levels increase only 2.6-fold. Further iodide uptake begin to increase at 24 h, whereas NIS protein increases at 36 h. These dissociations between uptake activity and NIS protein levels suggest variability in NIS activity.
Dai et al. (9) reported the existence of a putative consensus sequence for cAMP-dependent protein kinase phosphorylation on the cytoplasmic domain of NIS, suggesting that NIS activity may be modulated by cAMP-dependent protein phosphorylation. Furthermore, Marcocci et al. reported the superinduction of iodide transport in FRTL-5 cells by actinomycin D (18). TSH induces synthesis of different proteins between early phase (3–6 h after the addition of TSH) and late phase (12–24 h after TSH) (6, 18). Marcocci et al. (18) observed that actinomycin D inhibits TSH-stimulated I- accumulation when present during the early phase, but paradoxically increases TSH-stimulated I- accumulation when added during the late phase. They proposed that this superinduction may be attributable to inhibited synthesis of a repressor of I- accumulation (18).
These reports suggest that although, as indicated in this report, the number of NIS molecules is increased by TSH, there are unknown factors that regulate NIS activity in thyrocytes. If so, it is possible to interpret that the low iodine uptake observed upon treatment with cycloheximide results not only from a low NIS protein level, but also from the lack of synthesis of an activator of NIS.
The stimulation of iodine transport by TSH may conceivably involve mechanisms such as increased NIS protein, activation of NIS protein, or increased recycling of the protein; at present, distinction among these possibilities is limited. Further, clarification of the activation mechanism of NIS by TSH may contribute to the evaluation, diagnosis, and treatment of thyroid disorders, especially Graves’ disease and thyroid neoplasms.
Received October 11, 1996.
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) or 60 h (X).
I- efflux was measured as described in
Materials and Methods.
