Disease relevance of Tg

• The congenital goiter mutation is linked to the thyroglobulin gene in the mouse [1].
• Transformation of rat thyroid cells with polyoma virus middle T antigen results in loss of the thyroid-differentiated phenotype, measured as the expression of the thyroglobulin (Tg), thyroperoxidase (TPO), and sodium/iodide symporter (NIS) genes [2].
• The ectopic tissue buds ventrolaterally into the adjacent mesenchyme, and less extensively into the tracheal lumen, forming follicle-like structures that accumulate thyroglobulin [3].
• A single amino acid change in the acetylcholinesterase-like domain of thyroglobulin causes congenital goiter with hypothyroidism in the cog/cog mouse: a model of human endoplasmic reticulum storage diseases [4].
• Delineation of five thyroglobulin T cell epitopes with pathogenic potential in experimental autoimmune thyroiditis [5].

Psychiatry related information on Tg

• The heavy (H) and light (L) chains of murine monoclonal autoantibody 62 reacting with thyroglobulin independently express idiotypic (Id) determinants that are very similar if not identical with the Id62 expressed on the intact protein [6].

High impact information on Tg

• Also a large supply of iodine and of thyroid hormone is stored into the Tg molecule and available for secretion on demand [7].
• Characteristically these patients exhibit hereditary congenital goiter with relatively low Tg levels that do not increase after stimulation with bovine TSH [7].
• In another subject molecular studies revealed that exon 4 was missing from the major Tg transcript due to a cytosine to guanine transversion at position minus 3 in the acceptor splice site of intron 3 [7].
• The point mutation is removed by the preferential accumulation of a 171 nt deleted Tg mRNA [7].
• We found anti-DNA Abs that reacted to several different antigens, such as phosphatidylserine, myelin basic protein, thyroglobulin, histone, insulin, cytochrome C, and beta-galactosidase [8].

Chemical compound and disease context of Tg

• A synthetic peptide based on a sequence containing thyroxine at position 2553 in thyroglobulin (Tg), and already shown to be recognized by two clonotypically distinct murine Tg autoreactive T cell hybridomas, can trigger primed lymph node cells to transfer thyroiditis to naive recipients [9].
• Although very effective at preventing thyroid infiltrates in mice immunized with mouse thyroglobulin and complete Freund's adjuvant and in spontaneous models of thyroiditis and sialoadenitis, it completely failed to modify experimental autoimmune thyroiditis (EAT) induced in mice immunized with mouse thyroglobulin and lipopolysaccharide [10].
• Nor was mortality reduced after challenge with either E. coli V2019 or K. pneumoniae Caroli, even though the active immunization of mice with purified FeAero (ferric aerobactin) conjugated with thyroglobulin as followed by a rise in systemic anti-FeAero antibodies [11].

Biological context of Tg

• We report in this paper the cloning of TTF-2, a DNA binding protein that recognizes sites on both Tg and TPO promoters [12].
• These results indicate that the structural gene for thyroglobulin is on chromosome 15 and suggest that a mutation at the site of the TG gene is the basis of the cog defect [1].
• Consistent with this hypothesis, the DN CREB transgene inhibited the expression of an array of genes including thyroglobulin, thyroperoxidase, and the TSH receptor in semiquantitative RT-PCR experiments [13].
• Thyroid gland morphogenesis initiates normally, but follicle formation and thyroglobulin processing are abnormal at late gestation [14].
• Comparison of the complete sequences reveals that cog/cog mice express a Leu-2263 --> Pro missense mutation in the acetylcholinesterase-homology domain of Tg [4].

Anatomical context of Tg

• Expression of thyroglobulin (Tg) and thyroperoxidase (TPO) genes in thyroid follicular cells occurs in the mouse at embryonic day (E)14 [12].
• Heterologous expression studies in COS cells indicate that cog Tg exhibits a severe defect in exit from the ER [4].
• This study reaffirms the predictive value of A(k)-binding motifs in epitope mapping and doubles the number of known pathogenic T cell determinants in Tg that are now found scattered throughout the length of this large autoantigen [5].
• In addition, four of 22 tumors co-express thyroglobulin (a non-neuroendocrine follicular epithelial cell marker) and calcitonin (a neuroendocrine marker) in a subset of the tumor cells [15].
• The FRTL-5/TA cell line was the least differentiated one as thyroglobulin mRNA was detectable in only minute amounts and thyroid peroxidase expression could not be measured [16].

Associations of Tg with chemical compounds

• We demonstrate that the reintroduction of Pax8 in PCPy cells is sufficient to activate expression of the endogenous genes encoding thyroglobulin, thyroperoxidase, and sodium/iodide symporter [2].
• Thyroid glands of TSHR-KO mice produced uniodinated thyroglobulin, but the ability to concentrate and organify iodide could be restored to TSHR-KO thyroids when cultured in the presence of the adenylate cyclase agonist forskolin [17].
• Newly synthesized thyroglobulin (Tg), the major secretory glycoprotein of the thyroid gland, folds and homodimerizes in the endoplasmic reticulum (ER) before its export to the site of iodination, where it serves as the precursor for thyroid hormone synthesis [4].
• An animal model of constitutive activation of the thyroid cAMP cascade has been obtained by generating transgenic mice expressing the adenosine receptor (Tg-A2aR) under the control of the thyroglobulin promoter [18].
• Thyroids from mutant mice are hypertrophied, deficient in colloid, show a reduced accumulation of iodine that is partially susceptible to perchlorate ion discharge, have modestly elevated serum immunoreactive thyroglobulin (Tg) levels, but are markedly deficient in glandular immunoreactive Tg content [19].

Physical interactions of Tg

• Moreover, blocking experiments demonstrated that SC involves class I major histocompatibility complex and thyroglobulin (Tg) antigens [20].

Regulatory relationships of Tg

• Strategies that have been employed successfully in animal models include adenoviral mediated expression of thymidine kinase under control of a thyroglobulin promoter, similarly expression of the cytokine IL-2, and perhaps most effectively, expression of IL-12 [21].
• Effector cells from either IFN-gamma(+/+) or IFN-gamma(-/-) donor mice activated with mouse thyroglobulin and anti-IL-2R mAb induced severe granulomatous EAT [22].
• To determine whether HMGI proteins are also required for in vivo thyroid carcinogenesis, mice carrying a disrupted HMGI-C gene (pygmy mice) were either treated with radioactive iodine or crossed with transgenic mice carrying the E7 papilloma virus oncogene under the transcriptional control of thyroglobulin gene promoter [23].

Other interactions of Tg

• Moreover, we show that Pax8 and TTF-1 cooperate in the activation of the thyroglobulin promoter and that additional thyroid-specific mechanism(s) are involved in such a cooperation [2].
• The Tgn locus is syntenic with the c-myc protooncogene locus (Myc) in the mouse as in the rat and man [1].
• The Tgn locus was positioned proximal to the Ly-6 locus on Chr 15 [24].
• We had previously generated a transgenic mouse model in which the cAMP cascade was permanently stimulated in thyroid cells by an adenosine A2a receptor (Tg-A2aR model) [25].
• These cells also express an asialoglycoprotein receptor, a receptor involved in Tg endocytosis in the thyroid, and a Tg transcript smaller than the 8.3-kb thyroidal form [26].

Analytical, diagnostic and therapeutic context of Tg

• Site-directed mutagenesis of cog Tg to convert the single amino acid back to Leu-2263 restores normal Tg secretion [4].
• Autoradiography showed 125I was incorporated only into Tg within recognizable follicular lumina of thyroids from +/cog mice [27].
• Reverse transcriptase PCR showed that suppression of Pax-8 by Tg is correlated with reduced expression of bcl-2 apoptosis suppressor [26].
• A panel of mouse-rat cell hybrids was used to determine the chromosomal localization of the rat thyroglobulin gene by the Southern blotting method [28].
• Tissue studies confirm that there is an absent Tg peak at gel filtration, and virtually no immunoassayable Tg is present in the tissue extracts [7].

References