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)

Gene rearrangements activating the RET proto-oncogene are frequently associated with human thyroid carcinomas belonging to the papillary subtype. These arrangements cause the fusion of the tyrosine-kinase domain of RET to the 5'-terminal region of different genes creating the RET/PTC chimeric oncogenes. Here we report the generation of transgenic mice lines expressing the RET/PTC1 oncogene under the control of the thyroid-specific rat thyroglobulin promoter. RET/PTC1-transgenic mice developed thyroid tumors displaying the histological aspect of papillary carcinomas. These tumors were slowly progressive and did not cause premature death of the animals. Two additional mice developed areas of thyroid hyperplasia. Immunohistochemical and reverse-transcriptase polymerase chain reaction analyses confirmed the thyroid-specific expression of the transgene. Given the frequency of activating rearrangements of RET in human papillary thyroid carcinomas we conclude that this animal system could be a good model for studying the neoplastic progression of thyroid carcinomas.
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PMID:Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. 862 3

The most frequent genetic alterations described thus far in human papillary thyroid carcinomas are somatic rearrangements of the RET proto-oncogene, which generate the chimeric RET/PTC oncogenes. We recently found that the expression of the RET/PTC1 oncogene blocked the expression of the thyroid-differentiated phenotype in rat thyroid epithelial cell line PC CI 3 (PC). Here, we show that this block occurs at a transcriptional level; indeed, the thyroid-specific thyroglobulin and thyroperoxidase gene promoters were inactive in PC-PTC cells. Specific transcription factors, namely, TTF-1 and Pax-8, regulate the expression of differentiated functions in thyroid cells. Here, we show that Pax-8 is expressed at reduced levels in PC-PTC cells and that its adoptive overexpression is unable to restore the activity of target promoters. In contrast, TTF-1 expression is unaltered in PC-PTC cells; however, by using a synthetic promoter that contains its specific target sequence, we demonstrate that TTF-1 is inactive in PC-PTC cells. We conclude that the RET/PTC1 oncogene alters the expression of the thyroid-differentiated phenotype by at least two different mechanisms, ie., down-regulation of Pax-8 protein and mRNA expression and impaired function of TTF-1 and Pax-8, which occurs at a posttranslational level.
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PMID:Expression of the RET/PTC1 oncogene impairs the activity of TTF-1 and Pax-8 thyroid transcription factors. 943 93

The RET/PTC oncogene, a rearranged form of the RET proto-oncogene, has been found to be associated with human papillary thyroid carcinomas. To investigate whether RET/PTC causes papillary thyroid carcinoma, we generated a transgenic mouse model of papillary thyroid carcinoma with targeted expression of RET/PTC1 in the thyroid gland. Thyroid tumors in these RET/PTC1 transgenic mice are characterized by a slow growth rate, thyroid-stimulating hormone (TSH)-responsive tumor progression, and loss of radioiodide-concentrating activity despite continued expression of thyroglobulin (Tg). The time of tumor onset appears to be dependent on the expression level of RET/PTC1 in these transgenic mice. In high-copy RET/PTC1 transgenic mice, cellular abnormalities, including a slightly increased proliferation rate, aberrant follicle formation, and loss of radioiodide-concentrating activity, can be readily identified at embryological day 18. To identify which signaling pathway or pathways perturbed by RET/PTC1 are essential for RET/PTC1 to induce tumor development, we generated transgenic mice carrying a thyroid-targeted RET/PTC1 triple mutant, which contains tyrosine to phenylalanine mutations at tyrosine residues 294, 404, and 451. Initial characterization of the thyroid glands of these RET/PTC1 triple-mutant transgenic mice showed no change in follicular morphology or radioiodide-concentrating activity. This finding suggests that signaling pathways mediated by one or more of these three phosphotyrosine binding sites are essential for RET/PTC1 to induce thyroid tumor development. Finally, in order to investigate whether tumors induced by RET/PTC3 are more aggressive than those tumors induced by RET/PTC1, we also generated thyroid-targeted RET/PTC3 transgenic mice.
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PMID:Thyroid carcinomas in RET/PTC transgenic mice. 1002 6

Several reports have indicated that protein kinase C (PKC) is an important regulator of proliferation in thyroid cells. Unlike TSH, the mitogenic effects of phorbol esters are accompanied by de-differentiation. The role of individual PKC isoforms in thyroid cell proliferation and differentiation has not been examined. Recent studies have implicated the atypical PKCzeta, a phorbol ester-unresponsive isozyme, in cell proliferation, death, and survival. We overexpressed PKCzeta in Wistar rat thyroid (WRT) cells and determined that PKCzeta conferred TSH-independent DNA synthesis and cell proliferation. Cells overexpressing PKCzeta show higher levels of phosphorylated p42/p44 MAPK compared with vector-transfected cells. Experiments using a luciferase reporter for Elk-1 revealed that PKCzeta overexpressing cells exhibit higher basal Elk-1 transcriptional activity than vector-transfected control cells. Interestingly, stimulation of Elk-1 transcriptional activity by MEK1, a p42/p44 MAPK kinase, was significantly enhanced in cells overexpressing PKCzeta. Strikingly, TSH retained the ability to stimulate Tg expression in cells expressing PKCzeta. These results suggest that PKCzeta stimulates TSH-independent mitogenesis through a p42/p44 MAPK-dependent pathway. Unlike overexpression of Ras or phorbol ester treatment, PKC overexpression does not impair thyroglobulin (Tg) expression.
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PMID:Atypical protein kinase C-zeta stimulates thyrotropin-independent proliferation in rat thyroid cells. 1061 33

The ras family members and the tyrosine kinases RET and TRK are frequently activated in human tumors of the thyroid gland. To ascertain the effects of these oncogenes in cultured thyroid cells we have generated expression vectors containing activated versions of the three genes under the control of the thyroid-specific thyroglobulin gene promoter. Here we show that the expression of the three oncogenes differently affects thyroid differentiation. While the TRK-T1 oncogene interferes with the capability of thyroid cells of trapping iodide and only marginally affects thyroglobulin gene expression, both RET/PTC3 and N-ras(Gln61-Lys) induce a dramatic reduction of thyroglobulin mRNA and alleviate TSH dependency for cellular growth. However, none of the three oncogenes is able to induce the appearance of neoplastic transformation markers, such as growth in semisolid medium and tumorigenicity in athymic mice. This indicates that genetic events additional to TRK, RET, or N-ras activation are required for fully malignant transformation of thyroid cells.
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PMID:Human N-ras, TRK-T1, and RET/PTC3 oncogenes, driven by a thyroglobulin promoter, differently affect the expression of differentiation markers and the proliferation of thyroid epithelial cells. 1082 36

Divergent endocrine-neuroendocrine differentiation in thyroid carcinoma occurs in mixed medullary-follicular carcinomas (MMFC). Less than 40 cases of MMFC have been reported having highly heterogeneous patterns of growth. Classical medullary carcinoma areas may be intermingled with follicles or papillae or even oxyphilic and solid areas. Calcitonin and thyroglobulin are expressed in different cell populations. Presence of the latter suggests a potential usefulness of radioiodine treatment. The clinical behavior of MMFC does not differ from that of ordinary medullary carcinoma. The histogenesis of MMFC is controversial. The genetic analysis of the 2 neoplastic components showed that they are not derived from a common precursor, but rather display remarkable differences in the genetic profile (RET mutations and allelic losses). In addition, in some cases the follicular component was found to be oligo/polyclonal and therefore possibly hyperplastic rather than neoplastic. The follicular cells may have grown into the medullary carcinoma, after acquiring some molecular defect, being "hostage" of the true neoplastic (medullary) component.
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PMID:Thyroid carcinomas with mixed follicular and C-cell differentiation patterns. 1083 11

Thyroid nodule genesis may be considered as an amplification of thyroid heterogeneity due to genetic and/or epigenetic mechanisms. We classified the thyroid nodules in five types with distinct histological features: hyperplastic, neoplastic, colloid, cystic and thyroiditic nodules. Hyperplastic: Thyrocyte proliferation is under the control of TSH but several other paracrine and autocrine factors are secreted by follicular cells, the stromal apparatus and the lymphocytes, which are implicated in initiation and perpetuation of thyroid hyperplasia. Growth occurs mainly through TSHR, cAMP and PKA. Constitutive cAMP overproduction has been shown to be due to point mutation of the TSHR or Gs protein, producing overgrowth and hyperfunction. Neoplastic: Several activated oncogenes have been identified in thyroid malignancies. Oncogenes relevant to the thyroid carcinogenesis are: mutated TSHR and gsp (constitutive activation of cAMP); TRK (receptor for NGF); RET/PTC (phosphorylation of tyrosine kinase receptor)--an isoform of this oncogene is induced by radiation: ras (it encodes Gs proteins transducing mitogenic signals); and c-MET (receptor for hepatocyte growth factor). The evolution of a differentiated thyroid cancer towards an undifferentiated cancer is due to a mutation of a family of proteins (i.e., p53), which acts as a brake, preventing the genomic instability of cancer. It is suggested that a tumor initiates by RET or ras and possibly progresses--as a result of additional mutations and by p53 mutation--to anaplastic carcinoma. Colloid: Flattening of the epithelium and dilatation of follicles containing viscous material--made up by a concentrated solution of thyroglobulin (hTg)--is the characteristic of the colloid nodule. A defect of intraluminal reabsorption of hTg has been suggested but not proven. Experimentally, a load of iodine is able to change thyroid hyperplasia to a colloid feature; however, a load of iodine is rarely found in the clinical history of patients. A new clue to the pathogenesis comes from the finding that a relevant part of the colloid (10-20%) is made up of insoluble globules, where hTg is compacted in a polymeric form. It is suggested that stocking hTg into globules is defective in colloid nodules, leading to enormous enlargement of the follicle. Cystic: It is estimated that between 15 and 40% of thyroid nodules are partly or entirely cystic. The 'true cyst' is rare; most of the so-called cystic nodules are 'pseudocysts', which follow necrosis and colliquation. Necrosis issues as an imbalance between growth and the precisely regulated process of angiogenesis. More recently, the VEGF/VPF has been found to be at the origin of recent and recurrent cysts. Immunotoxic and apoptotic mechanisms have also been suggested. Chemical analysis of cystic fluid showed a 'denatured' and 'serum-like' pattern suggesting different mechanisms in the pathogenesis of the pseudocystic thyroid nodules. Thyroiditic: Nodular lymphocytic thyroiditis (NLT) includes two different entities: 1) lymphocyte thyroiditis growing as a nodule in a hyperplastic or normal gland, and 2) lymphocyte thyroiditis associated in the same nodule with other nodular diseases of the thyroid: papillary thyroid carcinoma and lymphoma have been found to be associated to chronic lymphocytic thyroiditis.
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PMID:Pathogenesis of thyroid nodules: histological classification? 1123 84

The risk of thyroid papillary carcinoma is increased by external radiation particularly in children under 15 years of age as shown by a marked increase in those exposed to radiation after Chernobyl. We were recently confronted in Belgium over a short period with four patients (3 F, 1 M) with papillary thyroid carcinoma who were aged 10 years, 2 months, 2 years and 6 years when the Chernobyl accident occurred. We thus raise the question of a possible relationship. The patients were aged 17, 11, 10, 19 years at presentation. They all presented fortuitously over 3 years which was a very unusual increase in our extensive experience in thyroid surgery (62 cases of thyroid cancer among 1014 thyroidectomies in adults vs 4 cases in 18 children since the Chernobyl accident in 1986). Two out of the four patients had psammoma bodies (identifiable on CT scanning and ultrasound) and thyroglobulin autoantibodies (TgAb). The first patient had positive lymph nodes at the time of surgery. The incidence of thyroid cancers in Belarus and Ukraine rose just 4 years after the Chernobyl disaster; because radioactive clouds passed over Belgium, we wonder whether the occurrence of thyroid cancer in our patients could be related to this irradiation. The mechanism of increased incidence of radiation-induced thyroid cancer is thought to be due to rearrangement of the tyrosine kinase domains of the RET and TTK genes. The other important similarities in our patients are the presence of psammoma bodies that can be visualized on radiological examination and the presence of TgAb that are more frequent in differentiated thyroid cancers. Whether or not these cases reflect an increased incidence in the population as a whole, clinicians must remain vigilant for this rare but curable cancer in young patients, especially if suggestive radiological features or TgAb are present.
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PMID:Occurrence of thyroid papillary carcinoma in young patients. A Chernobyl connection? 1139 70

Classic genetic rearrangements in papillary carcinoma of the thyroid involve the RET- or TRK proto-oncogenes. We report a novel chromosomal translocation t(3;5)(q12;p15.3), confirmed by fluorescence in situ hybridization, in a multifocal follicular variant of a papillary carcinoma of the thyroid in a 79-year-old woman, with skin metastases as a presenting symptom. Three years earlier, another cutaneous metastasis on her scalp was misdiagnosed as hidradenoma. Four tumour foci were recognized in the thyroid, two with a follicular variant of papillary carcinoma. To detect loss of heterozygosity, 14 chromosomes were investigated with 59 microsatellite markers. A clonal relationship was detected between the two foci of tumour in the thyroid gland containing follicular variant of papillary carcinoma and one of the skin lesions tested, all demonstrating loss of heterozygosity (LOH) in the same region of chromosome 22. Based on earlier reports, the low rate of LOH detected is in agreement with the diagnosis papillary carcinoma of the thyroid. Whole body scintigraphy performed after ablative therapy with radioiodine revealed multiple metastases in the lungs and skeleton. After repeated radioiodine therapy, thyroglobulin under thyroxine suppression became undetectable and post-therapeutic scintigraphy revealed important regression of metastases.
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PMID:A novel chromosomal translocation t(3;5)(q12;p15.3) and loss of heterozygosity on chromosome 22 in a multifocal follicular variant of papillary thyroid carcinoma presenting with skin metastases. 1167 39

A novel human thyroid papillary carcinoma cell line (FB-2) has been established and characterized. FB-2 cells harbor the RET/PTC1 chimeric oncogene in which the RET kinase domain is fused to the H4 gene. FB-2 cells neither formed colonies in semisolid media nor induced tumors after heterotransplant into severe combined immunodeficient mice. However, HMGI(Y), HMGI-C and c-myc genes, which are associated to thyroid cell transformation, were abundantly expressed in FB-2 cells but not in normal thyroid cells. FB-2 cells only partially retained the differentiated thyroid phenotype. In fact, the PAX-8 gene, which codes for a transcriptional factor required for thyroid cell differentiation, was expressed, while thyroglobulin, TSH-receptor and thyroperoxidase genes were not. Moreover, FB-2 cells produced high levels of interleukin (IL)-6 and IL-8.
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PMID:Establishment of a non-tumorigenic papillary thyroid cell line (FB-2) carrying the RET/PTC1 rearrangement. 1180 85


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