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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 10 5692-5697
Copyright © 2005 by The Endocrine Society

Modulation of Thyroid-Specific Gene Expression in Normal and Nodular Human Thyroid Tissues from Adults: An in Vivo Effect of Thyrotropin

Rocco Bruno1, Elisabetta Ferretti1, Emanuele Tosi, Franco Arturi, Paolo Giannasio, Tiziana Mattei, Angela Scipioni, Ivan Presta, Roberta Morisi, Alberto Gulino, Sebastiano Filetti and Diego Russo

Dipartimento di Scienze Cliniche (T.M., A.S., E.T., R.M., S.F.) and Dipartimento di Medicina Sperimentale e Patologia (E.F., A.G.), Università La Sapienza, 00161 Rome, Italy; Neuromed Institute (A.G.), 86077 Pozzilli, Italy; Ospedale di Tinchi-Pisticci (R.B., P.G.), 75020 Matera, Italy; and Dipartimento di Medicina Sperimentale e Clinica (F.A., I.P.) and Dipartimento di Scienze Farmacobiologiche (D.R.), Università di Catanzaro Magna Graecia, 88100 Catanzaro, Italy

Address all correspondence and requests for reprints to: Dr. Sebastiano Filetti, Dipartimento di Scienze Cliniche, Clinica Medica 2, Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy. E-mail: sebastiano.filetti{at}uniroma1.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Evidence from in vitro studies or animal models has shown that TSH affects thyrocytes by thyroid-specific expression modulation.

Objective: The objective of our study was to analyze the role of TSH in human thyroid gene expression in vivo.

Design/Setting: Thirty-nine normal thyroid tissues were collected at the same center.

Study Subjects: Patients were divided into two groups based on serum TSH levels: 17 with normal TSH levels (1–4 mU/liter; group 1) and 22 with TSH levels below 0.5 mU/liter (group 2).

Intervention: Group 2 underwent thyroidectomy after suppressive L-T4 therapy.

Main Outcome Measures: mRNA levels of thyroid genes such as sodium/iodide symporter (NIS), apical iodide transporter, pendrin, thyroglobulin, thyroperoxidase, TSH receptor, paired box transcription factor 8, and thyroid transcription factor-1 were evaluated by quantitative PCR.

Results: The reduction of TSH stimulation causes decreases in NIS and apical iodide transporter gene expression in normal tissues and more limited reductions in thyroglobulin, thyroperoxidase, and paired box transcription factor 8, but it has no significant effect on TSH receptor, pendrin, or thyroid transcription factor-1. Comparison of NIS levels in normal and nodular tissues from the same patient confirmed that it is differentially expressed in nodules only in the presence of normal TSH (P < 0.01). In patients with suppressed TSH, nodular NIS levels were similar to those in normal tissues.

Conclusions: Our data represent the first demonstration in human thyroid tissues that TSH contributes to the regulation of thyrocyte differentiation by modulating thyroid gene levels. It exerts a particularly important effect on the transcription of NIS, which becomes very low after prolonged TSH suppression.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
TSH IS THE main regulator of thyroid gland physiology. It affects iodide uptake, thyroid hormone synthesis and release, thyrocyte proliferation, and glandular blood flow (1). Most of these effects are mediated by TSH modulation of the expression of several thyroid-specific genes, including those that encode thyroglobulin (Tg) (2), thyroperoxidase (TPO) (3), the sodium/iodide symporter (NIS) (4), and the TSH receptor (TSH-R) (5). TSH also seems to regulate the expression of genes encoding the thyroid-specific transcription factors, thyroid transcription factor-1 (TTF-1) (6), paired box 8 transcription factor (PAX8) (7), and hematopoietically expressed homeobox (8), whereas no conclusive data have been reported on its regulatory effect on the more recently identified iodine metabolism proteins, thyroid oxidase and pendrin, as well as the apical iodide transporter (AIT-B) (9, 10, 11, 12). The evidence for these effects, however, is based predominantly on the study of in vitro thyroid cell models (in many cases, nonhuman) and, to a lesser extent, on in vivo transgenic or knockout mice models. In a critical analysis of data regarding the control of thyrocyte proliferation, Kimura et al. (13) highlighted discrepancies among findings derived from different thyrocyte systems and warned that extrapolation of these in vitro mechanistic data to the normal human thyroid cell is unacceptable in the absence of independent validation.

In the present study we investigated the long-term effects of TSH suppression on the main molecular markers of thyroid cell differentiation in an in vivo model of normal human thyroid tissue. Before surgical removal, these tissues had been exposed for at least 6 months to various levels of serum TSH (normal vs. low-absent). We found that TSH is an absolute prerequisite for the maintenance of NIS and AIT-B gene expression. The expression of other genes (Tg, TPO, and PAX8) was also regulated by TSH, but detectable levels persisted even in the absence of the hormone. In contrast, TSH-R, pendrin, and TTF-1 genes do not appear to be under the control of TSH, at least not at the mRNA level.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients and tissues

The protocol for this study was approved by the local ethics committee, and informed patient consent was obtained for all procedures. Specimens of thyroid tissue were collected from 39 patients undergoing surgery for the removal of thyroid nodules (solitary or multinodular goiters). All patients lived in an area characterized by moderate iodine deficiency. The nodules were classified as cold adenomas or carcinomas based on scintigraphic features and World Health Organization histological criteria (14). Nodular and normal (nonnodular) tissue specimens were collected from each patient and snap-frozen in liquid nitrogen. To exclude contamination from the normal nonnodular tissues, 8-µm-thick frozen sections of each sample were microdissected after xylene dehydration using a laser beam (MT-5000 laser microdissection; Nikon, Melville, NY) and picked up by the capturing caps.

Patients were divided into two groups. Those in group 1 (n = 17) were operated on shortly after the nodular disease had been diagnosed, without receiving any pharmacological treatment. Serum TSH levels in this group were consistently within the normal range (1.0–4.0 mU/liter). In contrast, group 2 (n = 22) underwent thyroidectomy after at least 6 months of closely monitored suppressive L-T4 therapy, and serum TSH had remained consistently below 0.5 mU/liter. Table 1Go summarizes the characteristics of each patient included in the study, including serum TSH levels assayed and the pathological diagnosis of the thyroid nodules.


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  		TABLE 1. Clinical and histological characteristics of the human thyroid tissue samples examined

 
Determination of mRNA levels using real-time RT-PCR

Total RNA was extracted from the cells using the RNA Fast kit (M-Medical S.p.A, Florence, Italy) according to the manufacturer’s instructions. Two micrograms of total RNA were reverse transcribed in a 20-µl reaction volume containing 200 U Moloney murine leukemia virus reverse transcriptase, 40 U ribonuclease inhibitor, 10 mmol/liter dA/T/C/G, 3 mM MgCl2, 50 mM Tris-HCl (pH 8.3), 75 mM KCl, and 600 ng random hexamers (Invitrogen Life Technologies, Inc., Paisley, UK). The cDNA were then diluted 1:10 in nuclease-free H2O (Invitrogen Life Technologies, Inc., Milan, Italy). Quantitative evaluation of mRNA was performed by real-time quantitative PCR in an ABI PRISM 7700 Sequence Detector (Applied Biosystems, Foster City, CA), which scans 96 sample tubes/assay. In accordance with the manufacturer’s instructions, each tube (reaction mixture volume, 25 µl) contained the cDNA equivalent of 25 ng total RNA, 12.5 µl TaqMan Universal PCR Master Mix (Applied Biosystems), 200 µM TaqMan probe, and 900 µM primer for each of the genes evaluated [NIS, AIT-B, pendrin, Tg, TPO, TSH receptor (TSH-R), PAX8, and TTF-1]. Oligonucleotide primers and probes for the genes analyzed and the endogenous control were purchased from Applied Biosystems. The following thermal cycler parameters were used: incubation at 50 C for 2 min and denaturing at 95 C for 10 min, followed by 40 cycles of amplification (denaturation at 95 C for 15 sec and annealing/extension at 60 C for 1 min). A standard run curve was generated for each amplification using six serial dilutions of a cDNA mixture expressing all the genes analyzed. All amplification reactions were performed in triplicate, and the averages of the threshold cycles were used to interpolate standard curves and calculate the amount of transcript in samples (SDS software, version 1.7a; Applied Biosystems). Quantification results were expressed, in arbitrary units, as the ratio of the target quantity to the quantity of the calibrator. All values were normalized to three endogenous controls, glyceraldehyde-3-phosphate dehydrogenase, ß2-microglobulin, and ß-actin, with similar results.

Statistical analysis

Results are expressed as the mean ± SE. Statistical differences were analyzed with the Mann-Whitney nonparametric test. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
We analyzed a series of human thyroid tissues, normal and pathological, to identify the in vivo effects of TSH on the transcription of several thyroid-specific genes. The tissues were collected from patients undergoing thyroidectomy for benign or malignant nodular disease. Nodular and nonnodular (normal) samples were collected from each patient. The patients were divided into two groups based on serum TSH levels measured at least twice during the 6 months preceding surgery and on the day of surgery. In all patients in group 1, TSH levels were consistently within the normal range (1–4 mU/liter). Those in group 2 had levels consistently below the arbitrary cutoff level of 0.5 mU/liter.

First, we used real-time RT-PCR to analyze total RNA extracted from the normal thyroid tissue specimens of patients from the two groups. In group 2 nonnodular tissues (from patients with low-absent TSH levels), the levels of expression of the various genes varied widely. The highest levels detected were those of the Tg gene, whereas the NIS and AIT-B genes displayed the lowest levels (Fig. 1Go). These data strongly suggest that the two iodide transporter genes, NIS and AIT-B, are the only ones that require stable TSH stimulation for expression (at the transcript level) in normal adult thyrocytes. Similar results (data not shown) were obtained when we limited our analysis to the nine specimens from group 2 patients with serum TSH levels of 0.1 mU/liter or less (see Table 1Go).



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  		FIG. 1. Expression of thyroid-specific gene transcript in normal thyroid samples from patients with low-absent TSH (group 2). For each gene, mRNA expression levels measured by quantitative RT-PCR are expressed as relative quantities, in arbitrary units (mean ± SE) after normalization with three endogenous controls (see Patients and Methods).

 
Next, we compared the expression levels of each gene (determined by quantitative PCR) in the nonnodular tissues from groups 1 and 2. As shown in Fig. 2Go and Table 2Go, the decrease in chronic exposure to TSH in group 2 caused remarkable reduction in the mRNA levels of NIS (–70% vs. levels in group 1) and TPO (–53%) genes and minor, but still significant, reduction in AIT-B (–26%), Tg (–25%), and PAX8 (–30%) gene expression. In contrast, it had no significant effect on the transcription of TSH-R, TTF-1, or pendrin.



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  		FIG. 2. Levels of mRNA for thyroid-specific genes in nonnodular thyroid tissues from patients with low-absent (group 2) vs. normal (group 1) serum TSH levels. For each gene, the mRNA level (mean ± SE) in tissue from group 1 is the reference value, represented on the graph as 100% (dashed line). The level for group 2, with low TSH levels ({square}), is expressed as a percentage with respect to the group 1 value. *, P < 0.01.

 

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  		TABLE 2. mRNA levels of thyroid-specific genes in normal thyroid tissues chronically exposed to different values of serum TSH

 
We then focused our attention on the transcription of NIS in nodular and nonnodular tissues from the same patients. We excluded data from patients with malignant nodules (see Table 1Go), because of potentially confounding effects of major abnormalities occurring during malignant transformation. Examination of the entire set of adenomatous nodules (14 in group 1 and 18 in group 2) revealed that NIS mRNA expression levels were decreased by approximately 45% compared with those in normal nonnodular tissues from the same patients, but no significant differences were observed for TPO, Tg, or TSH-R (Fig. 3AGo). The same trend was observed in group 1; NIS transcription in nodular tissues was even more suppressed (–60% compared with normal tissues), whereas TPO, Tg, and TSH-R mRNA levels were unchanged (Fig. 3BGo). In contrast, in the absence of adequate TSH stimulation (group 2), there were no significant differences between nodular and nonnodular tissues in the levels of any of the genes examined (Fig. 3CGo). The latter data were confirmed by a direct comparison of the expression levels of the genes in the nodular tissues of the two groups of patients (data not shown).



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  		FIG. 3. Levels of mRNA for NIS, TPO, Tg, and TSH-R in benign nodular vs. nonnodular thyroid tissues. For each gene, the mRNA level (mean ± SE) found in normal nonnodular tissue ({cjs2108}) is the reference value, represented on the graph as 100%. The corresponding level for nodular tissue (mean ± SE; {blacksquare}) is expressed as a percentage of the reference value. *, P < 0.01. Data from patients with malignant lesions (patients 3, 4, and 12 in group 1 and patients 22, 25, 27, and 31 in group 2; see Table 1Go) were excluded from this analysis. A, Analysis of all samples from groups 1 and 2 (n = 32). *, P < 0.05. B, Analysis of group 1 patients (n = 14). *, P < 0.05. C, Analysis of group 2 patients (n = 18).

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In this study we analyzed the mechanism of control of normal human thyroid cell differentiation, focusing on the role of TSH on thyroid-specific gene expression occurring in adulthood. Most of the available information on this topic is based on observations made in in vitro studies of cultured cells and validated in transgenic and knockout mouse models (15, 16, 17). Findings from pathological human tissues (i.e. from patients with Graves’ disease, toxic adenomas, or iodine-deficient goiter) have been extrapolated to define the role of TSH in normal thyrocyte-specific gene expression. In a critical evaluation of the various in vitro models used for this purpose, Kimura et al. (13) stressed that the mechanism underlying TSH control of thyrocyte proliferation can vary considerably depending on the model adopted. In contrast, species differences represent the major limitation to the use of in vivo animal models. The use of pathological human thyroid tissues to evaluate gene/protein expression also has its drawbacks. For example, if tissues from patients with Graves’ disease are used, there is no way to compare findings with those of normal nonhyperplastic tissue from the same patient. For toxic adenoma, gene expression profiles can vary widely depending on the presence or absence of TSH-R/gsp mutations in these tissues (18). Furthermore, phenotypic differences have been described in adenomas carrying various TSH-R mutations, including some involving the activation of different signal transduction pathways (19, 20). Finally, the study of hyperplastic goiters associated with iodine deficiency is complicated by the fact that iodine itself exerts well-demonstrated direct effects on several markers of thyroid differentiation, above all NIS expression (21).

Our study is the first attempt to investigate a series of normal adult human thyroid tissues collected from patients exposed to normal (1–4 mU/liter) or low (<0.5 mU/liter) serum levels of TSH for the 6 months preceding surgery. All tissue samples were collected at the same center, and microdissection was performed to exclude all types of contamination or abnormal features (i.e. lymphocyte infiltration) from the normal nonnodular tissues. In addition, the patients enrolled in this study had stable levels of serum TSH for at least 6 months before surgery, as documented by at least two assays, the latter performed on the day of surgery. Considering a minimal margin of error for the TSH assay, we excluded patients whose values fell within the borderline zone of 0.5 and 1 mU/liter. As an added control, the results for group 2 tissues (i.e. those from patients with TSH levels <0.5 mU/liter) were compared with those for the subset of group 2 patients with very low TSH levels (<0.1 mU/liter), and no significant differences were found in the expression levels of any of the genes examined (data not shown).

We believe that this model provides a unique opportunity for characterizing TSH modulation of in vivo gene expression in the adult human thyroid gland. For the first time we describe the effects in humans of long-term suppression of TSH on normal and nodular thyroid cells, whereas no information is provided on the effect of acute TSH stimulation or overstimulation, and modification of protein expression.

Our findings demonstrate that TSH does indeed chronically modulate the expression of Tg, TPO, NIS, AIT-B, and PAX8 genes. However, even in the absence of TSH, mRNA for all these genes, with the exceptions of NIS and AIT-B, can still be detected. In adulthood, TSH is capable of regulating the expression of several thyrocyte differentiation markers, but in most cases it is not strictly necessary for their expression. It appears to play a similar role in the normal morphological development of the thyroid (22). Normal thyroid gland development and preserved expression of Tg, TTF-1, TTF-2, and PAX8 genes have also been described in TSH-R knockout mouse models (16, 17), in which only TPO and NIS genes appeared to be TSH dependent. In the normal adult thyroid, our findings indicate that TSH is essential for the expression of both NIS and AIT-B, which illustrates the key role it plays, primarily at the transcriptional level, in the control of thyrocyte iodine metabolism. However, the activity of the NIS promoter is known to be under the control of a complex network of regulatory proteins that includes multiple signal transduction effectors and transcription factors (23, 24). Much less is currently known about the control of AIT-B expression. No acute stimulatory TSH effects have been observed in studies of human thyrocytes in culture, and this is consistent with the finding of similar AIT-B expression levels in normal and hyperfunctioning thyroid tissues (11, 12). At present, however, the actual contribution of this gene to intrathyroidal iodine metabolism and its putative role as an oncosuppressor in normal and transformed thyrocytes are still being debated (11, 12, 25).

The other finding that emerged from our examination of normal thyroid tissues involved the stimulatory effect of TSH on the transcription of almost all markers of thyroid cell differentiation. This result was to some extent expected, based on previously reported data derived from the study of cultured thyrocytes and/or animal models of human disease (see introduction). However, our results show that even subtle changes in TSH levels are able to elicit a significant increase in thyroid-specific gene expression. Again, the effect on NIS gene expression was particularly evident, as confirmed by our analysis of NIS transcript levels in benign nodules. In group 2, the levels of NIS transcript found in these nodules were comparable to those observed in the nonnodular tissues from the same patient. The decisive influence of serum TSH on NIS expression was also observed in a previous study of ours conducted on tissues collected from patients with toxic or nontoxic multinodular goiters (26). Therefore, in the absence of data on levels of serum TSH, gene or protein expression data obtained by the comparative analyses of paired pathological and normal thyroid tissues should be interpreted with caution.

In conclusion, our data provide evidence that TSH contributes to the regulation of thyrocyte differentiation in normal adult thyroid tissues by acting on the transcription of almost all the thyroid-specific genes. Its influence on the NIS gene is particularly important; indeed, the prolonged absence of TSH stimulation diminishes NIS expression to very low levels. This model of normal human thyroid tissues can be used with gene array/proteomic techniques in future studies aimed at increasing our understanding of the mechanisms underlying the physiological control of thyroid function in adulthood.


   Footnotes
 
This work was supported by grants from Ministero della Salute and Ministero dell’Istruzione, Università e Ricerca (MIUR-COFIN 2004; to S.F.) and a grant from Ministero dell’Istruzione, Università e Ricerca (MIUR-COFIN 2003; to D.R.).

First Published Online August 2, 2005

1 R.B. and E.F. contributed equally to this work. Back

Abbreviations: AIT-B, Apical iodide transporter; NIS, sodium/iodide symporter; PAX, paired box transcription factor; Tg, thyroglobulin; TPO, thyroperoxidase; TSH-R, TSH receptor; TTF, thyroid transcription factor.

Received April 12, 2005.

Accepted July 21, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Spaulding SW 2000 Biological action of thyrotropin. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the thyroid: a fundamental and clinical text, 8th Ed. Philadelphia: Lippincott Williams & Wilkins; 227–233
  2. Van Heuverswyn B, Streydio C, Brocas H, Refetoff S, Dumont J, Vassart G 1984 Thyrotropin controls transcription of the thyroglobulin gene. Proc Natl Acad Sci USA 81:5941–5945[Abstract/Free Full Text]
  3. Nagayama Y, Yamashita S, Hirayu H, Izumi M, Uga T, Ishikawa N, Ito K, Nagataki S 1989 Control of thyroid peroxidase and thyroglobulin gene expression by thyrotropin in human cultured thyroid cells. J Clin Endocrinol Metab 68:1155–1159[Abstract]
  4. Saito T, Endo T, Kawaguchi A, Ikeda M, Nakazato M, Kogai T, Onaya T 1997 Increased expression of the Na+/I– symporter in cultured human thyroid cells exposed to thyrotropin and in Graves’ thyroid tissue. J Clin Endocrinol Metab 82:3331–3336[Abstract/Free Full Text]
  5. Maenhaut C, Brabant G, Vassart G, Dumont JE 1992 In vitro and in vivo regulation of thyrotropin receptor mRNA levels in dog and human thyroid cells. J Biol Chem 15:3000–3007
  6. Saito T, Endo T, Nakazato M, Kogai T, Onaya T 1997 Thyroid-stimulating hormone-induced down-regulation of thyroid transcription factor 1 in rat thyroid FRTL-5 cells. Endocrinology 138:602–606[Abstract/Free Full Text]
  7. Fabbro D, Pellizzari L, Mercuri F, Tell G, Damante G 1998 Pax-8 protein levels regulate thyroglobulin gene expression. J Mol Endocrinol 21:347–354[Abstract]
  8. Pellizzari L, D’Elia A, Rustighi A, Manfioletti G, Tell G, Damante G 2000 Expression and function of the homeodomain-containing protein Hex in thyroid cells. Nucleic Acids Res 28:2503–2511[Abstract/Free Full Text]
  9. Dupuy C, Pomerance M, Ohayon R, Noel-Hudson MS, Deme D, Chaaraoui M, Francon J, Virion A 2000 Thyroid oxidase (THOX2) gene expression in the rat thyroid cell line FRTL-5. Biochem Biophys Res Commun 277:287–292[CrossRef][Medline]
  10. Royaux IE, Suzuki K, Mori A, Katoh R, Everett LA, Kohn LD, Green ED 2000 Pendrin, the protein encoded by the Pendred syndrome gene (PDS), is an apical porter of iodide in the thyroid and is regulated by thyroglobulin in FRTL-5 cells. Endocrinology 141:839–845[Abstract/Free Full Text]
  11. Lacroix L, Pourcher T, Magnon C, Bellon N, Talbot M, Intaraphairot T, Caillou B, Schlumberger M, Bidart JM 2004 Expression of the apical iodide transporter in human thyroid tissues: a comparison study with other iodide transporters. J Clin Endocrinol Metab 89:1423–1428[Abstract/Free Full Text]
  12. Porra V, Ferraro-Peyret C, Durand C, Selmi-Ruby S, Giroud H, Berger-Dutrieux N, Decaussin M, Peix JL, Bournaud C, Orgiazzi J, Borson-Chazot F, Dante R, Rousset B 2005 Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas. J Clin Endocrinol Metab 90:3028–3035[Abstract/Free Full Text]
  13. Kimura T, Van Keymeulen A, Golstein J, Fusco A, Dumont JE, Roger P 2001 Regulation of thyroid cell proliferation by TSH and other factors: a critical evaluation of in vitro models. Endocr Rev 22:631–656[Abstract/Free Full Text]
  14. Hedinger C, Williams ED, Sobin LH 1989 The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer 63:908–911[CrossRef][Medline]
  15. Goffard JC, Jin L, Mircescu H, Van Hummelen P, Ledent C, Dumont JE, Corvilain B 2004 Gene expression profile in thyroid of transgenic mice overexpressing the adenosine receptor 2a. Mol Endocrinol 18:194–213[Abstract/Free Full Text]
  16. Marians RC, Ng L, Blair HC, Unger P, Graves PN, Davies TF 2002 Defining thyrotropin-dependent and -independent steps of thyroid hormone synthesis by using thyrotropin receptor-null mice. Proc Natl Acad Sci USA 99:15776–15781[Abstract/Free Full Text]
  17. Postiglione MP, Parlato R, Rodriguez-Malln A, Rosica A, Mithbaokar P, Maresca M, Marians RC, Davies TF, Zannini MS, De Felice M, Di Lauro R 2002 Role of the thyroid stimulating hormone receptor signaling in development and differentiation of the thyroid gland. Proc Natl Acad Sci USA 99:15462–15467[Abstract/Free Full Text]
  18. Eszlinger M, Krohn K, Frenzel R, Kropf S, Tonjes A, Paschke R 2004 Gene expression analysis reveals evidence for inactivation of the TGF-ß signaling cascade in autonomously functioning thyroid nodules. Oncogene 23:795–804[CrossRef][Medline]
  19. Arturi F, Scarpelli D, Coco A, Sacco R, Bruno R, Filetti S, Russo D 2003 Thyrotropin receptor mutations and thyroid hyperfunctioning adenomas ten years after their first discovery: unresolved questions. Thyroid 13:341–343[CrossRef][Medline]
  20. Corvilain B, Van Sande J, Dumont JE, Vassart G 2001 Somatic and germline mutations of the TSH receptor and thyroid diseases. Clin Endocrinol (Oxf) 55:143–158[CrossRef][Medline]
  21. Uyttersprot N, Pelgrims N, Carrasco N, Gervy C, Maenhaut C, Dumont JE, Miot F 1997 Moderate doses of iodide in vivo inhibit cell proliferation and the expression of thyroperoxidase and Na+/I– symporter mRNAs in dog thyroid. Mol Cell Endocrinol 131:195–203[CrossRef][Medline]
  22. Dumont JE, Lamy F, Roger P, Maenhaut C 1992 Physiological and pathological regulation of thyroid cell proliferation and differentiation by Thyrotropin and other factors. Physiol Rev 72:667–697[Free Full Text]
  23. Dohan O, Carrasco N 2003 Advances in Na+/I– symporter (NIS) research in the thyroid and beyond. Mol Cell Endocrinol 213:59–70[CrossRef][Medline]
  24. Puppin C, Arturi F, Ferretti E, Russo D, Sacco R, Tell G, Damante G, Filetti S 2004 Transcriptional regulation of human NIS gene: a role for Redox factor-1. Endocrinology 145:1290–1293[Abstract/Free Full Text]
  25. Rodriguez AM, Perron B, Lacroix L, Caillou B, Leblanc G, Schlumberger M, Bidart JM, Pourcher T 2002 Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes. J Clin Endocrinol Metab 87:3500–3503[Abstract/Free Full Text]
  26. Russo D, Bulotta S, Bruno R, Arturi F, Giannasio P, Derwahl M, Bidart JM, Schlumberger M, Filetti S 2001 Sodium/iodide symporter (NIS) and pendrin are expressed differently in hot and cold nodules of thyroid toxic multinodular goiter. Eur J Endocrinol 145:591–597[Abstract]



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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals