Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Megalin mediates transcytosis of thyroglobulin (Tg), the thyroid hormone precursor, resulting in its passage into the bloodstream. The process involves especially hormone-poor Tg, which may favour hormone secretion by preventing competition with hormone-rich Tg for proteolytic degradation. To gain more insight into the role of megalin, here we studied thyroid function and histology in megalin deficient mice compared with WT mice. As expected from the knowledge that megalin mediates Tg transcytosis, serum Tg levels were significantly reduced in homozygous (megalin-/-) mice, which, more importantly, were found to be hypothyroid, as demonstrated by significantly reduced serum free thyroxine and significantly increased serum thyroid stimulating hormone (TSH) levels. In heterozygous (megalin+/-) mice, in which megalin expression was normal, thyroid function was unaffected. Although the serological phenotype in megalin-/- mice was not associated with histological alterations or goiter, our results support a major role of megalin in thyroid hormone secretion.
Mol Cell Endocrinol 2005 May 31
PMID:Thyroid dysfunction in megalin deficient mice. 1587 30

Aim-To evaluate the expression of ribosomal cistrons in human thyroid epithelial cells (TECs) of patients with Grave's disease, Hashimoto's thyroiditis and benign and malignant tumours of the thyroid gland.Methods-TEC nucleoli were investigated in fine needle biopsy specimens from 10 controls, 39 patients with Grave's disease, 15 with Hashimoto's thyroiditis, 56 with benign, and 15 with malignant tumours of the thyroid. A one step silver staining method was applied. In most cases serum concentrations of thyroxine and triiodothyronine as well as goitre size were determined. In every case 100 TECs were evaluated for the mean numbers of nucleoli and for the average number of argyrophilic nucleolar organiser regions (AgNORs) per nucleus.Results-NORs were activated in all patients, but not in controls. The numbers of AgNORs in patients with Grave's disease were closely correlated with thyroxine or triiodothyronine, or both, concentrations and with the size of the thyroid. In patients with Hashimoto's thyroiditis about 30% of TECs nucleoli did not contain AgNORs, whereas others were heavily impregnated with silver. Compared with controls and benign tumours, the nucleoli of carcinomatous TECs were larger and irregular in shape. The mean number of AgNORs per nucleus in malignant cells was higher than that in their benign counterparts.Conclusions-The mechanism by which NORs are activated in TECs varies depending on the type of lesion. The higher AgNOR score in TECs from malignant tumours can be used to distinguish them from their benign counterparts.
Clin Mol Pathol 1996 Aug
PMID:Interphase ribosomal RNA cistron staining in thyroid epithelial cells in Grave's disease, Hashimoto's thyroiditis and benign and malignant tumours of the thyroid gland. 1669 83

Angiogenesis entails the sprouting of new vessels from pre-existing vasculature. In adults, angiogenesis occurs in the thyroid gland during disease processes such as hyperplastic goiter, Graves disease, thyroiditis, and cancer. In the present study multiple morphologic characteristics of microvessels were measured in and compared between 18 cases of Graves disease, 29 cases of Hashimoto's thyroiditis, and 15 control cases. All histologic sections were immunostained for CD31. Quantification of microvessel density (MVD), major axis length, minor axis length, area, perimeter and shape factor was performed by image analysis. MVD was increased significantly in both forms of autoimmune thyroid disease. Significantly higher values were found in Graves disease in comparison to Hashimoto's thyroiditis. In contrast, major axis length, minor axis length, and area had significantly higher values in Hashimoto's thyroiditis than in Graves disease. The statistical analysis revealed MVD as the unique significant morphometric factor discriminating the two autoimmune entities.
Appl Immunohistochem Mol Morphol 2006 Jun
PMID:Comparative study of angiogenesis in thyroid glands with Graves disease and Hashimoto's thyroiditis. 1678 91

The aim of this study was to evaluate in vivo the antiproliferative effect of an inhibitor of isoprenoids metabolism, lovastatin, in an experimental model of propylthiouracil-induced goiter. In thyroid cells, thyrotropin (TSH)-induced proliferation requires active isoprenoid synthesis, and the HMG-CoA reductase inhibitors have antiproliferative effects in vitro. Propylthiouracil treatment (PTU) of rats led to thyroid hypertrophy and hyperplasia by TSH-induced activation of the mitogen-activated protein kinase (MAPK) pathway. Immunohistochemistry showed an increased number of proliferating cell nuclear antigen (PCNA)-positive cells in the thyroid gland of PTU-treated rats. Moreover, the phosphorylation of ERK1 and ERK2 was increased in the extract from goiter tissue as compared with the thyroid tissue of untreated rats. To determine whether the inhibition of selected pro-survival pathways (i.e., p21ras-MAPK) was sufficient to affect goitrogenesis, thyroids from 12 PTU-treated rats were injected in vivo with an adenovirus transducing a dominant-negative ras gene (Rad-L61.S186) and another set of 12 rats were injected with a pharmacological inhibitor of MAPK (PD98059). Both Rad-L61.S186 and PD98059 were able to inhibit the PTU-induced goiter. It is interesting to note that lovastatin, when administered in drinking water, significantly prevented the thyroid gland enlargement. Therefore, lovastatin-treated thyroid glands were significantly smaller than those treated with PTU alone. In addition, the lovastatin-treated glands also showed a decreased expression of phosphorylated ERK1/2 and a number of PCNA-positive cells. Our data suggest that lovastatin is an efficient inhibitor of goitrogenesis and provide a rationale for innovative therapeutic strategies employing statins in the treatment of nodular goiter in humans.
J Mol Med (Berl) 2006 Nov
PMID:HMG-CoA reductase inhibitors inhibit rat propylthiouracil-induced goiter by modulating the ras-MAPK pathway. 1694 2

To evaluate the significance of antithyroid antibodie levels, five hundred and twenty-six patients with thyroid diseases and 292 health subjects from Yuci District, Shanxi Province, China, were studied. Serum levels were determined for thyroid hormone receptor antibody (TRAb), microsomal antibody (TMAb) and thyroglobulin antibody (TGAb). Among patients, the percentages for nodular goiter and thyroid adenoma, Graves' disease, and Hashimoto's thyroiditis are 44.1%, 19.6% and 17.7%, respectively. The ratios of female to male were 2.0 to 15.6. Antibody-positive patients for TMAb, TGAb and TRAb were detectable as 94.6%, 76.3% and 20.4% for Hashimoto's thyroiditis, and 40.0%, 30.0% and 90.3% for Graves's disease. In conclusion, the high levels of the TRAb in Graves' disease, and those of the TGAb/TMAb in Hashimoto's thyroiditis and idiopathic hypothyroidism are meaningful for characterizing the epidemiological basis of the diseases and for using as prognostic indicators for the relapse in individual patients.
Cell Mol Immunol 2007 Jun
PMID:Autoantibodies highly increased in patients with thyroid dysfunction. 1760 79

It has been suggested that a thyroglobulin (Tg)-R19K missense mutation may be a newly identified cause of human congenital goiter, which is surprising for this seemingly conservative substitution. Here, we have examined the intracellular fate of recombinant mutant Tg expressed in COS-7 cells. Incorporation of the R19K mutation largely blocked Tg secretion, and this mutant was approximately 90% degraded intracellularly over a 24-h period after synthesis. Before its degradation, the Tg-R19K mutant exhibited abnormally increased association with molecular chaperones BiP, calnexin, and protein disulfide isomerase, and was unable to undergo anterograde advance from the endoplasmic reticulum (ER) through the Golgi complex. Inhibitors of proteasomal proteolysis and ER mannosidase-I both prevented ER-associated degradation of the Tg-R19K mutant and increased its association with ER molecular chaperones. ER quality control around Tg residue 19 is not dependent upon charge but upon side-chain packing, because Tg-R19Q was efficiently secreted. Whereas a Tg mutant truncated after residue 174 folds sufficiently well to escape ER quality control, introduction of the R19K point mutation blocked its secretion. The data indicate that the R19K mutation induces local misfolding in the amino-terminal domain of Tg that has global effects on Tg transport and thyroid hormonogenesis.
Mol Endocrinol 2008 Feb
PMID:Defective protein folding and intracellular retention of thyroglobulin-R19K mutant as a cause of human congenital goiter. 1791 55

Despite evidence for a conserved role of thyroid-stimulating hormone (TSH) in regulating vertebrate thyroid function, molecular data on thyroid responses to TSH are mainly limited to mammalian species. In this study, we examined histological and molecular changes in the thyroid of Xenopus laevis tadpoles during a 12-day treatment with 20mg/l perchlorate (PER) and 50mg/l ethylenethiourea (ETU). Inhibition of thyroid hormone (TH) synthesis by PER and ETU was evident from developmental retardation, reduced expression of TH-regulated genes and up-regulation of tshb-A mRNA. Thyroid histopathology revealed goiters with strikingly different follicular morphologies following PER and ETU treatment. Using real-time PCR, we analyzed thyroids sampled on day 12 for differential expression of 60 candidate genes. Further temporal analyses were performed for a subset of 14 genes. Relative to the control, PER and ETU treatment modulated the expression of 51 and 49 transcripts, respectively. Particularly genes related to TH synthesis and protein metabolism were similarly affected by PER and ETU. However, several genes were differentially expressed in PER- and ETU-treated tadpoles. Specifically, goiter formation in the PER treatment was associated with low expression of genes related to DNA replication but high expression of negative growth regulators. Results from this work provide for the first time a characterization of gene expression profiles during goitrogenesis in a non-mammalian vertebrate model. Overall, our data suggest that, in addition to TSH over-stimulation, further mechanisms related to the mode of goitrogen action contribute to the regulation of thyroid gene expression.
Mol Cell Endocrinol 2009 Jan 27
PMID:Perchlorate and ethylenethiourea induce different histological and molecular alterations in a non-mammalian vertebrate model of thyroid goitrogenesis. 1880 9

G protein-coupled receptors (GPCRs) are involved in the pathophysiology of a wide range of diseases and constitute an attractive therapeutic target. In the thyroid gland, TSH receptor (TSHR), a member of the GPCR family, is a major regulator of thyroid differentiation and function. Alterations in TSHR activity are often involved in the development of pathologies such as thyroid cancer and thyroid enlargement (goiter). Here we show that DREAM (downstream regulatory element antagonist modulator) modulates TSHR activity through a direct protein-protein interaction that promotes coupling between the receptor and Galphas. In transgenic mice, DREAM overexpression provokes a marked enlargement of the thyroid gland. Increased levels of DREAM protein were observed in human multinodular goiters, suggesting a novel etiopathogenic mechanism in nodular development in humans. Taken together, these findings identify a mechanism for the control of TSHR activity and provide a new approach for the study and treatment of thyroid pathologies associated with impaired TSHR function.
Mol Endocrinol 2009 Jun
PMID:The DREAM protein is associated with thyroid enlargement and nodular development. 1929 42

Disorders in the proliferation and apoptosis of thyrocytes may induce goitre, adenoma and carcinoma in the thyroid. The Wnt/beta-catenin pathway has been demonstrated to be involved in the regulation of cell proliferation, differentiation and apoptosis in various cell lines. The regulatory mechanism on the proliferation and differentiation of thyrocytes is not well characterized. In the present study, a GSK-3beta-targeting RNA interference (RNAi) adenovirus vector was constructed and delivered to primary human thyrocytes. Results showed that the expression of beta-catenin protein in primary human thyrocytes was increased after GSK-3beta-targeting RNAi adenovirus infection, the proliferation of primary human thyrocytes was significantly stimulated using Bromodeoxyuridine (BrdU) assay, while cell apoptosis was slightly affected which was observed through flow cytometry. It is concluded that the Wnt/beta-catenin pathway plays a significant role in the regulation of the proliferation of primary human thyrocytes.
Mol Biol Rep 2010 Jul
PMID:Regulation of GSK-3 beta in the proliferation and apoptosis of human thyrocytes investigated using a GSK-3 beta-targeting RNAi adenovirus expression vector: involvement the Wnt/beta-catenin pathway. 1975 60

Thyroglobulin (TG) defects due to TG gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. This dyshormonogenesis displays a wide phenotype variation and is characterized usually by: the presence of congenital goiter or goiter appearing shortly after birth, high (131)I uptake, negative perchlorate discharge test, low serum TG and elevated serum TSH with simultaneous low serum T(4) and low, normal or high serum T(3). Mutations in TG gene have been also reported associated with endemic and euthyroid nonendemic simple goiter. TG gene defects are inherited in an autosomal recessive manner and affected individuals are either homozygous or compound heterozygous for mutations. Up to now, 50 mutations have been identified and characterized in the human TG: 23 missense mutations, 10 nonsense mutations, 5 single and 1 large nucleotide deletions, 1 single nucleotide insertion and 10 splice site mutations. The functional consequences of this mutations could be structural changes in the protein molecule that alter the normal protein folding, assembly and biosynthesis of thyroid hormones, leading to a marked reduction in the ability to export the protein from the endoplasmic reticulum.
Mol Cell Endocrinol 2010 Jun 30
PMID:Genetics and phenomics of hypothyroidism and goiter due to thyroglobulin mutations. 2009 66


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