Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An autoimmune disease can be the cause of thyroid disfunction. Determination of autoantibodies titers is the best way of demonstrating its existence. We studied 172 thyroid patients (146 females, 26 males) with ages ranging from 15 to 81 years. Thyroid microsomal autoantibodies (TMA) were detected by a modified agglutination test (SERA-TEK kit, Ames Div); a dilution greater than or equal to 1/1600 was considered as diagnostic of autoimmune disease. Patients were classified according to morphological and functional status in 3 groups: GI = non toxic goiter, n = 98 (71 diffuse, 20 multi and 7 uninodular); GII = toxic goiter, n = 62 (52 diffuse, 4 multi, 2 uninodular and 4 subacute thyroiditis); G III = hypothyroidism, n = 12 (5 primary hypothyroidism and 7 chronic thyroiditis). A control group of 30 normal individuals, ages ranging from 19 to 85 years was also studied. Diagnostic titers of TMA were found in 30.8% of group I, 88.5% of group II, 91.6% of group III and only in 6.6% of controls. The high incidence of positive TMA in toxic diffuse goiter (96.1%) as well as in hypothyroid patients was expected since these are typical examples of thyroid autoimmune disease. In the non toxic goiter group, positive TMA were present in 50% of multinodular, 28% of uninodular and 25% of diffuse goiters and the incidence of positive TMA varied according to age, being higher over the age of 40 years and lower under the age of 20 years. We postulate that this unexpected high incidence of positive TMA in non toxic goiter is due to amelioration of chronic iodine deficiency inducing the expression of latent autoimmune disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Thyroid microsomal autoantibodies in thyroid disease: their value as an antigenic marker]. 251 89

It is well recognized that the use of external irradiation of the head and neck to treat patients with various non-thyroid disorders increases their risk of developing papillary thyroid carcinoma years after radiation exposure. An increased risk of thyroid cancer has also been reported in survivors of the atomic bombs in Japan, as well as in Marshall Island residents exposed to radiation during the testing of hydrogen bombs. More recently, exposure to radioactive fallout as a result of the Chernobyl nuclear reactor accident has clearly caused an enormous increase in the incidence of childhood thyroid carcinoma in Belarus, Ukraine, and, to a lesser extent, in the Russian Federation, starting in 1990. When clinical and epidemiological features of thyroid carcinomas diagnosed in Belarus after the Chernobyl accident are compared with those of naturally occurring thyroid carcinomas in patients of the same age group in Italy and France, it becomes apparent that the post-Chernobyl thyroid carcinomas were much less influenced by gender, virtually always papillary (solid and follicular variants), more aggressive at presentation and more frequently associated with thyroid autoimmunity. Gene mutations involving the RET proto-oncogene, and less frequently TRK, have been shown to be causative events specific for papillary cancer. RET activation was found in nearly 70% of the patients who developed papillary thyroid carcinomas following the Chernobyl accident. In addition to thyroid cancer, radiation-induced thyroid diseases include benign thyroid nodules, hypothyroidism and autoimmune thyroiditis, with or without thyroid insufficiency, as observed in populations after environmental exposure to radioisotopes of iodine and in the survivors of atomic bomb explosions. On this basis, the authors evaluated thyroid autoimmune phenomena in normal children exposed to radiation after the Chernobyl accident. The results demonstrated an increased prevalence of circulating thyroid antibodies not associated with significant thyroid dysfunction. This finding is consistent with the short period of follow-up, but it is highly likely that these children will develop clinical thyroid autoimmune diseases in the future. Therefore, screening programmes for this at-risk population should focus, not only on the detection of thyroid nodules and cancer, but also on the development of thyroid autoimmune diseases.
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PMID:Thyroid consequences of the Chernobyl nuclear accident. 1062 41

Autoregulation of thyroid hormone (TH) receptors (TRs) is a mechanism whereby a cell can regulate its responsiveness to TH. Nuclear coactivators (NCoAs) modulate TH action and may also be important for regulation of TR expression. We have determined the effect of TH withdrawal and treatment on the expression of different isoforms of TR as well as expression of the NCoAs SRC-1, TIF-2 and SRC-3 using quantitative real time polymerase chain reaction. In order to identify the effect that each TR isoform exerts over the expression of the other, NCoA and TR transcripts were measured in liver and heart tissue from wild type mice or mice with deletion of either TR isoform or SRC-1 genes. In liver, regulation of TR beta1 and TR alpha2 subtype expression is inversely related to TH levels and the regulation of TR beta expression is, in part, controlled by TR alpha. In the heart, the opposite is the case, regulation of TR alpha2 and TR beta1 isoform expression is directly related to TH levels and this regulation is primarily controlled by TR alpha. Although NCoAs are, in general, increased in response to hypothyroidism or in states of TH resistance, SRC-1 specifically does not regulate TR isoform expression. We have demonstrated that TR isoforms and NCoAs are autoregulated transcription factors with tissue specificity.
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PMID:Regulation of expression of thyroid hormone receptor isoforms and coactivators in liver and heart by thyroid hormone. 1278 4

Gain-of-function RET mutations are responsible for multiple endocrine neoplasia syndromes (MEN) 2A and 2B and familial medullary thyroid carcinoma (FMTC), whereas loss-of-function mutations are found in Hirschsprung disease. We report a new RET point mutation [R694Q (CGG-->CAG)], serendipitously found in a 23-yr-old woman with hypothyroidism due to atrophic Hashimoto's thyroiditis and primary ovarian failure, without altered calcitonin secretion. Familial history and clinical and biochemical evaluation of first-degree relatives were negative for FMTC, MEN 2A and 2B, and Hirschsprung disease. Genetic analysis showed that the mutation was inherited from the mother, who was submitted 2 yr before to thyroidectomy for goitrous Hashimoto's thyroiditis. Histological revision and immunohistochemical studies documented normal C cell number and morphology. We cloned the mutation in an expression vector encoding a full-length RET protein. The construct was transiently expressed in 293T cells in parallel with a wild-type RET and a C634R MEN 2A-associated RET mutant. Proteins were harvested from transfected cells, and tyrosine phosphorylation levels were assayed. The mutation did not exert significant potentiating effects on RET kinase. A focus assay was also performed on NIH3T3 fibroblasts; the mutant did not exert significant transforming activity. In conclusion, a new RET mutation was found in two subjects without any evidence of MEN and FMTC. In keeping with clinical data, transfection studies confirmed lack of activating activity. This serendipitous discovery, apparently devoid of oncogenic potential, underscores the problems that may be encountered in genomic studies on RET.
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PMID:A new germline RET mutation apparently devoid of transforming activity serendipitously discovered in a patient with atrophic autoimmune thyroiditis and primary ovarian failure. 1547 67

Thyroid hormone deficiency during the critical period of neural differentiation produces permanent and severe alterations in the morphology and function of the nervous system leading to cretinism. Perinatal hypothyroidism results in permanent alterations of hippocampal synaptic functions in adult rats consequently causing learning and memory impairment. Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that regulate essential cellular activities ranging from gene expression, mitosis, programmed cell death to plasticity and memory formation, but their involvement in perinatal hypothyroidism is not determined. The present work was designed to investigate MAPKs phosphorylation in hippocampus of congenital neonatal hypothyroid rats. Congenital hypothyroidism promotes an increase in extracellular signal-regulated kinases 1/2 (ERK 1/2) phosphorylation (+50%) and a decrease in p38(MAPK) phosphorylation (-50%) without changing in Jun N-terminal kinases (JNK) phosphorylation. Therefore, the congenital hypothyroidism model disturbs ERK 1/2 and p38(MAPK) phosphorylation pathways causing an important molecular alteration in the hippocampus. This event might be related, at least partially, to the deficits in hippocampal development and cognitive functions due neonatal congenital hypothyroidism.
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PMID:Congenital hypothyroidism alters the phosphorylation of ERK1/2 and p38MAPK in the hippocampus of neonatal rats. 1561 63

Thyroid hormones are critical for the development and maturation of the central nervous system. Insufficiency of thyroid hormones during development impairs performance on tasks of learning and memory that rely upon the hippocampus and impairs synaptic function in young hypothyroid animals. The present study was designed to determine if perturbations in synaptic function persist in adult euthyroid animals exposed developmentally to insufficient levels of hormone. Pre- and postnatal thyroid hormone insufficiency was induced by administration of 3 or 10 ppm propylthiouracil (PTU) to pregnant and lactating dams via the drinking water from gestation day (GD) 6 until postnatal day (PN) 30. This regimen produced a graded level of hormonal insufficiency in the dam and the offspring. Population spike and population excitatory postsynaptic potentials (EPSP) were recorded at the pyramidal cell layer and the stratum radiatum, respectively, in area CA1 of hippocampal slices from adult male offspring. PTU exposure increased baseline synaptic transmission, reduced paired-pulse facilitation, and increased the magnitude of the population spike long-term potentiation (LTP). Phosphorylation of the extracellular signal-regulated kinases (ERK1 and ERK2) was increased as a function of LTP stimulation in slices from PTU-exposed adult animals. On the other hand, no differences in the basal levels of synaptic proteins implicated in synaptic plasticity (total ERK, synapsin, growth-associated protein-43, and neurogranin) were detected. These results reinforce previous findings of persistent changes in synaptic function and, importantly extend these observations to moderate levels of thyroid hormone insufficiency that do not induce significant toxicity to the dams or the offspring. Such alterations in hippocampal synaptic function may contribute to persistent behavioral deficits associated with developmental hypothyroidism.
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PMID:Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency. 1567 45

In goiter, increased expression of growth factors and their receptors occurs. We have inhibited the action of some of these growth factors, alone and in combination, to determine which are important in goitrogenesis. Recombinant adenovirus vectors (RAds) expressing truncated, secreted forms of human Tie2 (RAd-sTie2) and vascular endothelial growth factor receptor 1 (RAd-sVEGFR1) or a truncated, dominant-negative fibroblast growth factor receptor 1 (RAdDN-FGFR1) were used. Goiters in mice were induced by feeding an iodide-deficient diet, containing methimazole and sodium perchlorate. RAds were administered to mice simultaneously with the goitrogenic regimen, which was continued for 14 d. RAd treatment did not significantly affect increases in TSH or reductions in thyroid hormone or thyroid hyperactivity seen in goitrogen-treated controls mice, suggesting no effect on pituitary or thyroid responses to hypothyroidism. In control goiters, a 4-fold increase in vascular volume accompanied a 2-fold increase in thyroid mass. Complete inhibition of these increases was found when animals were treated with the three RAds in combination. In thyroids from three RAd-treated animals, there was marked, significant inhibition of Tie2, FGFR1, VEGFR1, FGF-2, and VEGF expression, compared with control goiters. When used individually, RAdDN-FGFR1 partially prevented goiter and RAd-sVEGFR1 partially reduced vascular volume. Their effects were not additive. RAd-sTie2 did not reduce goiter mass or vascular volume when used alone but was essential for complete goiter inhibition. VEGF and VEGFR1 expression was reduced in these thyroids. Limitation of physiologic organ growth is complex, requiring inhibition of multiple, interdependent growth factor axes.
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PMID:Complete inhibition of goiter in mice requires combined gene therapy modification of angiopoietin, vascular endothelial growth factor, and fibroblast growth factor signaling. 1581 62

Childhood hypothyroidism causes growth arrest with delayed ossification and growth-plate dysgenesis, whereas thyrotoxicosis accelerates ossification and growth. Thyroid hormone (T(3)) regulates chondrocyte proliferation and is essential for hypertrophic differentiation. Fibroblast growth factors (FGFs) are also important regulators of chondrocyte proliferation and differentiation, and activating mutations of FGF receptor-3 (FGFR3) cause achondroplasia. We investigated the hypothesis that T(3) regulates chondrogenesis via FGFR3 in ATDC5 cells, which undergo a defined program of chondrogenesis. ATDC5 cells expressed two FGFR1, four FGFR2, and one FGFR3 mRNA splice variants throughout chondrogenesis, and expression of each isoform was stimulated by T(3) during the first 6-12 d of culture, when T(3) inhibited proliferation by 50%. FGFR3 expression was also increased in cells treated with T(3) for 21 d, when T(3) induced an earlier onset of hypertrophic differentiation and collagen X expression. FGFR3 expression was reduced in growth plates from T(3) receptor alpha-null mice, which exhibit skeletal hypothyroidism, but was increased in T(3) receptor beta(PV/PV) mice, which display skeletal thyrotoxicosis. These findings indicate that FGFR3 is a T(3)-target gene in chondrocytes. In further experiments, T(3) enhanced FGF2 and FGF18 activation of the MAPK-signaling pathway but inhibited their activation of signal transducer and activator of transcription-1. FGF9 did not activate MAPK or signal transducer and activator of transcription-1 pathways in the absence or presence of T(3). Thus, T(3) exerted differing effects on FGFR activation during chondrogenesis depending on which FGF ligand stimulated the FGFR and which downstream signaling pathway was activated. These studies identify novel interactions between T(3) and FGFs that regulate chondrocyte proliferation and differentiation during chondrogenesis.
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PMID:Thyroid hormones regulate fibroblast growth factor receptor signaling during chondrogenesis. 1615 Sep 8

Multiple endocrine neoplasia (MEN) is defined as concurrent neoplasia or hyperplasia in more than one endocrine gland. MEN is well known in humans and has also been reported in small animals. We report on a dog family of a mixed breed with Alaskan malamute as a major influence, where three members developed thyroid carcinomas and another dog had clinical signs mimicking the other three but without a confirmed diagnosis. The age of onset of the tumour was between 96-109 months. Clinical, biochemical and immunohistochemical examinations revealed that the affected individuals typically demonstrated symptoms including calcitonin positive thyroid cancer, hypothyroidism and chronic dermatitis. In addition, elevated serum calcium and multinodular adrenocortical hyperplasia were demonstrated in a single member. The diagnosis observed is similar to the familial form of medullary thyroid carcinoma (FMTC) in human. This is the first report of FMTC in dog. Up to 95% of FMTC and MEN2 is known to be caused by activating mutations in the RET gene. The dog Ret gene was analysed as a candidate in this pedigree. The complete dog Ret genomic sequence was predicted in silico. The lack of demonstratable Ret mutation suggests the involvement of alternative predisposing mutation in this pedigree. The unique occurrence of familial MTC makes this potentially an important model in further defining the genetic basis of MTC.
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PMID:A dog pedigree with familial medullary thyroid cancer. 1701 49

Herein we present the case of a 9-year-old girl who had an enlarged right lobe of the thyroid gland and sub-clinical hypothyroidism (thyroid stimulating hormone at 9.24 mIU/L). The patient had a history of unintentional exposure to radiation while her mother was receiving radionuclide therapy for diffuse toxic goiter. Ultrasonography of the young girl showed right lobe enlargement with diffuse coarse heterogenous echogenicity, compatible with a microcalcification pattern identified in both lobes of the thyroid gland. Histopathology of the tissue from a thyroidectomy revealed papillary thyroid carcinoma in the right lobe and chronic lymphocytic thyroiditis in the remaining tissue. Molecular pathology demonstrated an RET/PTC1 rearrangement in both tumor and non-tumorous tissue harboring thyroiditis. Considering the history of exposure and the characteristics of the thyroid pathology together, the PTC in this patient was likely a secondary-to-genetic alteration induced by external radiation. This case emphasizes the importance of stringent restrictions when giving radioactive iodine therapy to a patient with small children.
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PMID:Papillary carcinoma of the thyroid gland in a child of thyrotoxicosis patient receiving radioactive iodine therapy: report of a case. 1841 77


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