Thyroglobulin (Tg), the most important and abundant protein in thyroid follicles, is well known for its essential role in thyroid hormone synthesis. In addition to its conventional role as the precursor of thyroid hormones, we have uncovered a novel function of Tg as an endogenous regulator of follicular function over the past decade. The newly discovered negative feedback effect of Tg on follicular function observed in the rat and human thyroid provides an alternative explanation for the observation of follicle heterogeneity. Given the essential role of the regulatory effects of Tg, we consider that dysregulation of normal Tg function is associated with multiple human thyroid diseases including autoimmune thyroid disease and thyroid cancer. Additionally, extrathyroid Tg may serve a regulatory function in other organs. Further exploration of Tg action, especially at the molecular level, is needed to obtain a better understanding of both the physiological and pathological roles of Tg. 1. Introduction The thyroid gland is comprised of thyroid follicles, in which thyrocytes surround a follicular lumen with the apical surface of a thyrocyte facing the lumen while the basal surface faces a basket-like capillary network evenly surrounding each thyroid follicle. Thyroglobulin (Tg), which is well known as the macromolecular precursor of thyroid hormone, is the most important and abundant protein produced and stored in thyroid follicles [1]. In the last decade, in addition to its well-established role as the precursor of thyroid hormone, we have revealed important novel roles for Tg. We found that Tg can serve as a negative regulator of thyroid function-related genes and an inducer of thyrocyte growth. In this review, we will summarize these studies of newly recognized Tg action and discuss the potential involvement of Tg in the development of thyroid disorders. Despite enormous advances in understanding the structure and the role of Tg in hormonogenesis, our understanding of the molecular function of Tg remains incomplete. Therefore, we will also include discussion of unanswered questions regarding Tg in this review that we hope will inspire further studies. 2. The Synthesis of Tg and Secretion of Thyroid Hormones Tg is synthesized as a 12S molecule (330？kDa) and in its most stable state forms a 19S dimer (660？kDa). Biosynthesis of thyroid hormones and their release in the circulation include the following sequence of events [1, 2]. Iodide from the blood stream is concentrated by the sodium iodide symporter (NIS) [3] at the basolateral surface of a thyrocyte
References
[1]
G. Salvatore and H. Edelhoch, “Chemistry and biosythesis of thyroid iodoproteins,” in Hormonal Proteins and Peptides, C. H. Li, Ed., pp. 201–244, Academic Press, New York, NY, USA, 1973.
[2]
J. Robbins, J. E. Rall, and P. Gorden, “The thyroid and iodine metabolism,” in Duncan's Diseases of Metabolism, P. K. Bondy and L. E. Rosenberg, Eds., pp. 1009–1104, Saunders, Philadelphia, Pa, USA, 1974.
[3]
G. Dai, O. Levy, and N. Carrasco, “Cloning and characterization of the thyroid iodide transporter,” Nature, vol. 379, no. 6564, pp. 458–460, 1996.
[4]
L. A. Everett, B. Glaser, J. C. Beck et al., “Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS),” Nature Genetics, vol. 17, no. 4, pp. 411–422, 1997.
[5]
I. E. Royaux, K. Suzuki, A. Mori et al., “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, vol. 141, no. 2, pp. 839–845, 2000.
[6]
R. Ekholm, G. Engstrom, L. E. Ericson, and A. Melander, “Exocytosis of protein into the thyroid follicle lumen: an early effect of TSH,” Endocrinology, vol. 97, no. 2, pp. 337–346, 1975.
[7]
L. E. Ericson and B. R. Johansson, “Early effects of thyroid stimulating hormone (TSH) on exocytosis and endocytosis in the thyroid,” Acta Endocrinologica, vol. 86, no. 1, pp. 112–118, 1977.
[8]
P. G. Malan, J. Strang, and W. Tong, “TSH initiation of hormone secretion by rat thyroid lobes in vitro,” Endocrinology, vol. 95, no. 2, pp. 397–405, 1974.
[9]
Y. Mizukami, T. Hashimoto, A. Nonomura et al., “Immunohistochemical demonstration of thyrotropin (TSH)-receptor in normal and diseased human thyroid tissues using monoclonal antibody against recombinant human TSH-receptor protein,” Journal of Clinical Endocrinology and Metabolism, vol. 79, no. 2, pp. 616–619, 1994.
[10]
K. Tanaka, H. Inoue, H. Miki, K. Komaki, and Y. Monden, “Heterogeneous distribution of thyrotrophin receptor messenger ribonucleic acid (TSH-R mRNA) in papillary thyroid carcinomas detected by in situ hybridization,” Clinical Endocrinology, vol. 44, no. 3, pp. 259–267, 1996.
[11]
S. Aeschimann, P. A. Kopp, E. T. Kimura et al., “Morphological and functional polymorphism within clonal thyroid nodules,” Journal of Clinical Endocrinology and Metabolism, vol. 77, no. 3, pp. 846–851, 1993.
[12]
H. Gerber, H. J. Peter, and H. Studer, “Diffusion of thyroglobulin in the follicular colloid. (Minireview),” Endocrinologia Experimentalis, vol. 20, no. 1, pp. 23–33, 1986.
[13]
H. Gerber, H. J. Peter, and H. Studer, “Age-related failure of endocytosis may be the pathogenetic mechanism responsible for 'cold' follicle formation in the aging mouse thyroid,” Endocrinology, vol. 120, no. 5, pp. 1758–1764, 1987.
[14]
S. Smeds, H. J. Peter, and E. Jortso, “Naturally occurring clones of cells with high intrinsic proliferation potential within the follicular epithelium of mouse thyroids,” Cancer Research, vol. 47, no. 6, pp. 1646–1651, 1987.
[15]
K. Suzuki, H. Matsumoto, M. Kobayashi, A. Kawaoi, K. Asayama, and S. I. Moriyama, “Immunohistochemical localization of copper-zinc and manganese superoxide dismutases in diisopropanolnitrosamine-induced rat thyroid lesions,” Acta Histochemica et Cytochemica, vol. 24, no. 1, pp. 69–73, 1991.
[16]
K. Yamamoto, Y. Xue, R. Katoh, and A. Kawaoi, “Differential immunolocalization of thyroglobulin (Tg) in the follicular epithelium of rat thyroid glands and its kinetics under thyrotropin (TSH) stimulation—a quantitative immunoelectron microscopic analysis using post-embedding immunogold technique,” Acta Histochemica et Cytochemica, vol. 30, no. 2, pp. 147–155, 1997.
[17]
K. Suzuki, S. Lavaroni, A. Mori et al., “Autoregulation of thyroid-specific gene transcription by thyroglobulin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 14, pp. 8251–8256, 1998.
[18]
K. Suzuki, A. Mori, S. Lavaroni et al., “In vivo expression of thyroid transcription factor-1 RNA and its relation to thyroid function and follicular heterogeneity: identification of follicular thyroglobulin feedback suppressor of thyroid transcription factor-1 RNA levels and thyroglobulin synthesis,” Thyroid, vol. 9, no. 4, pp. 319–331, 1999.
[19]
K. Suzuki, A. Hemmi, R. Katoh, and A. Kawaoi, “Differential image analysis of proliferating cell nuclear antigen (PCNA) expression level during experimental thyroid carcinogenesis,” Acta Histochemica et Cytochemica, vol. 29, no. 2, pp. 99–105, 1996.
[20]
X. Yi, K. Yamamoto, L. Shu, R. Katoh, and A. Kawaoi, “Effects of propylthiouracil (PTU) administration on the synthesis and secretion of thyroglobulin in the rat thyroid gland: a quantitative immunoelectron microscopic study using immunogold technique,” Endocrine Pathology, vol. 8, no. 4, pp. 315–325, 1997.
[21]
L. D. Kohn, K. Suzuki, M. Nakazato, I. Royaux, and E. D. Green, “Effects of thyroglobulin and pendrin on iodide flux through the thyrocyte,” Trends in Endocrinology and Metabolism, vol. 12, no. 1, pp. 10–16, 2001.
[22]
D. F. Sellitti and K. Suzuki, “Intrinsic regulation of thyroid function by thyroglobulin,” Thyroid. In press.
[23]
K. Suzuki, A. Kawashima, A. Yoshihara et al., “Role of thyroglobulin on negative feedback autoregulation of thyroid follicular function and growth,” Journal of Endocrinology, vol. 209, no. 2, pp. 169–174, 2011.
[24]
K. Suzuki and L. D. Kohn, “Differential regulation of apical and basal iodide transporters in the thyroid by thyroglobulin,” Journal of Endocrinology, vol. 189, no. 2, pp. 247–255, 2006.
[25]
K. Suzuki, A. Mori, S. Lavaroni, R. Katoh, L. D. Kohn, and A. Kawaoi, “Thyroglobulin: a master regulator of follicular function via transcriptional suppression of thyroid specific genes,” Acta Histochemica et Cytochemica, vol. 32, no. 2, pp. 111–119, 1999.
[26]
K. Suzuki, A. Mori, S. Lavaroni et al., “Thyroglobulin regulates follicular function and heterogeneity by suppressing thyroid-specific gene expression,” Biochimie, vol. 81, no. 4, pp. 329–340, 1999.
[27]
K. Suzuki, A. Mori, J. Saito, E. Moriyama, L. Ullianich, and L. D. Kohn, “Follicular thyroglobulin suppresses iodide uptake by suppressing expression of the sodium/iodide symporter gene,” Endocrinology, vol. 140, no. 11, pp. 5422–5430, 1999.
[28]
K. Suzuki, M. Nakazato, L. Ulianich et al., “Thyroglobulin autoregulation of thyroid-specific gene expression and follicular function,” Reviews in Endocrine and Metabolic Disorders, vol. 1, no. 3, pp. 217–224, 2000.
[29]
A. Yoshihara, T. Hara, A. Kawashima et al., “Regulation of dual oxidase expression and H2O2 production by thyroglobulin,” Thyroid, vol. 22, no. 10, pp. 1054–1062, 2012.
[30]
Y. Ishido, K. Yamazaki, M. Kammori et al., “Thyroglobulin suppresses thyroid-specific gene expression in cultures of normal, but not neoplastic human thyroid follicular cells,” Journal of Clinical Endocrinology and Metabolism, 2014.
[31]
M. Sue, M. Hayashi, A. Kawashima et al., “Thyroglobulin (Tg) activates MAPK pathway to induce thyroid cell growth in the absence of TSH, insulin and serum,” Biochemical and Biophysical Research Communications, vol. 420, no. 3, pp. 611–615, 2012.
[32]
M. Nakazato, H.-K. Chung, L. Ulianich, A. Grassadonia, K. Suzuki, and L. D. Kohn, “Thyroglobulin repression of thyroid transcription factor 1 (TTF-1) gene expression is mediated by decreased DNA binding of nuclear factor I proteins which control constitutive TTF-1 expression,” Molecular and Cellular Biology, vol. 20, no. 22, pp. 8499–8512, 2000.
[33]
K. Suzuki, I. E. Royaux, L. A. Everett et al., “Expression of PDS/Pds, the Pendred syndrome gene, in endometrium,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 2, pp. 938–941, 2002.
[34]
F. Pacifico, N. Montuori, S. Mellone et al., “The RHL-1 subunit of the asialoglycoprotein receptor of thyroid cells: cellular localization and its role in thyroglobulin endocytosis,” Molecular and Cellular Endocrinology, vol. 208, no. 1-2, pp. 51–59, 2003.
[35]
R. J. Stockert, “The asialoglycoprotein receptor: relationships between structure, function, and expression,” Physiological Reviews, vol. 75, no. 3, pp. 591–609, 1995.
[36]
D. A. Wall and A. L. Hubbard, “Receptor-mediated endocytosis of asialoglycoproteins by rat liver hepatocytes: biochemical characterization of the endosomal compartments,” Journal of Cell Biology, vol. 101, no. 6, pp. 2104–2112, 1985.
[37]
L. Ulianich, K. Suzuki, A. Mori et al., “Follicular thyroglobulin (TG) suppression of thyroid-restricted genes involves the apical membrane asialoglycoprotein receptor and TG phosphorylation,” Journal of Biological Chemistry, vol. 274, no. 35, pp. 25099–25107, 1999.
[38]
S. S. Huang, M. A. Cerullo, F. W. Huang, and J. S. Huang, “Activated thyroglobulin possesses a transforming growth factor-β activity,” Journal of Biological Chemistry, vol. 273, no. 40, pp. 26036–26041, 1998.
[39]
D. F. Sellitti, K. Suzuki, S. Q. Doi et al., “Thyroglobulin increases cell proliferation and suppresses Pax-8 in mesangial cells,” Biochemical and Biophysical Research Communications, vol. 285, no. 3, pp. 795–799, 2001.
[40]
Y. Noguchi, N. Harii, C. Giuliani, I. Tatsuno, K. Suzuki, and L. D. Kohn, “Thyroglobulin (Tg) induces thyroid cell growth in a concentration-specific manner by a mechanism other than thyrotropin/cAMP stimulation,” Biochemical and Biophysical Research Communications, vol. 391, no. 1, pp. 890–894, 2010.
[41]
T. Kimura, A. van Keymeulen, J. Golstein, A. Fusco, J. E. Dumont, and P. P. Roger, “Regulation of thyroid cell proliferation by tsh and other factors: a critical evaluation of in vitro models,” Endocrine Reviews, vol. 22, no. 5, pp. 631–656, 2001.
[42]
T. Nedachi, M. Akahori, M. Ariga et al., “Tyrosine kinase and phosphatidylinositol 3-kinase activation are required for cyclic adenosine 3′,5′-monophosphate-dependent potentiation of deoxyribonucleic acid synthesis induced by insulin-like growth factor-I in FRTL-5 cells,” Endocrinology, vol. 141, no. 7, pp. 2429–2438, 2000.
[43]
S.-I. Takahashi, M. Conti, C. Prokop, J. J. van Wyk, and H. S. Earp III, “Thyrotropin and insulin-like growth factor I regulation of tyrosine phosphorylation in FRTL-5 cells: interaction between cAMP-dependent and growth factor-dependent signal transduction,” Journal of Biological Chemistry, vol. 266, no. 12, pp. 7834–7841, 1991.
[44]
K. Brix, R. Wirtz, and V. Herzog, “Paracrine interaction between hepatocytes and macrophages after extrathyroidal proteolysis of thyroglobulin,” Hepatology, vol. 26, no. 5, pp. 1232–1240, 1997.
[45]
D. F. Sellitti, T. Akamizu, S. Q. Doi et al., “Renal expression of two 'thyroid-specific' genes: thyrotropin receptor and thyroglobulin,” Experimental Nephrology, vol. 8, no. 4-5, pp. 235–243, 2000.
[46]
D. Plachov, K. Chowdhurry, C. Walther, D. Simon, J.-L. Guenet, and P. Gruss, “Pax8, a murine paired box gene expressed in the developing excretory system and thyroid gland,” Development, vol. 110, no. 2, pp. 643–651, 1990.
[47]
G. Zheng, M. Marino, J. Zhao, and R. T. McCluskey, “Megalin (gp330): a putative endocytic receptor for thyroglobulin (Tg),” Endocrinology, vol. 139, no. 3, pp. 1462–1465, 1998.
[48]
S. C. Jordan, B. Buckingham, R. Sakai, and D. Olson, “Studies of immune-complex glomerulonephritis mediated by human thyroglobulin,” New England Journal of Medicine, vol. 304, no. 20, pp. 1212–1215, 1981.
[49]
D. F. Sellitti, E. Puggina, C. Lagranha et al., “TGF-β-like transcriptional effects of thyroglobulin (Tg) in mouse mesangial cells,” Endocrine Journal, vol. 54, no. 3, pp. 449–458, 2007.
[50]
H. Wu, S. Suzuki, D. F. Sellitti et al., “Expression of a thyroglobulin (Tg) variant in mouse kidney glomerulus,” Biochemical and Biophysical Research Communications, vol. 389, no. 2, pp. 269–273, 2009.
