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)

Anaplastic large cell lymphomas (ALCL) are frequently associated with the t(2;5)(p23;q35). This translocation fuses the nucleophosmin (NPM) gene at 5q35, which encodes a nucleolar protein involved in shuttling ribonucleoproteins from the cytoplasm to the nucleus, to the anaplastic lymphoma kinase (ALK) gene at 2p23, encoding a tyrosine kinase receptor. In this report, we describe a typical case of ALCL whose malignant cells exhibited a novel (1;2)(q25;p23) translocation. These cells expressed ALK protein, but, in contrast to t(2;5)-positive ALCL (which show cytoplasmic, nuclear, and nucleolar staining), labeling was restricted to the malignant cell cytoplasm. Using a polymerase chain reaction (PCR)-based technique to walk on chromosome 2 from the known ALK gene across the breakpoint, we showed that the gene involved at 1q25 is TPM3, encoding a nonmuscular tropomyosin. We subsequently identified, using reverse transcription-PCR analysis of cases showing similar ALK cytoplasm-restricted staining, fusion of the ALK and TPM3 genes in 2 other cases of ALCL. The TPM3 gene has been previously found in papillary thyroid carcinomas as a fusion partner with the TRK kinase gene. We showed that TPM3 is constitutively expressed in lymphoid cell lines, suggesting that, in these t(1;2)-bearing ALCL cases, the TPM3 gene contributes an active promoter for ALK expression. Activation of the ALK catalytic domain probably results from homodimerization of the hybrid protein TPM3-ALK, through the TPM3 protein-protein interaction domain. The present cases of ALCL associated with a novel t(1;2)(q25;p23) demonstrate that at least one fusion partner other than NPM can activate the intracytoplasmic domain of the ALK kinase.
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PMID:A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation. 1021 6

Recent studies have mapped two susceptibility loci which appear to account for familial multinodular goitre (MNG1) and a variant of familial papillary thyroid cancer (PTC), with associated multinodular goitre (TCO). A Tasmanian family (Tas1) has been identified with an autosomal dominant form of PTC. This study has examined the MNG1 and TCO loci to determine if they are similarly predisposing the Tas1 family to PTC. Linkage analysis using identical microsatellite markers described in the two previous studies was used to determine the significance of these loci in the Tasmanian family. The resultant LOD scores were sufficiently negative using multipoint parametric analysis to exclude these two loci from involvement in the Tasmanian family. In addition, six candidate genes, RET, TRK, MET, TSHR, APC and PTEN were also excluded as susceptibility genes in Tas1 by using microsatellites that are positioned in or in close proximity to these genes. These results suggest that there are at least three susceptibility genes that predispose families to familial PTC.
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PMID:At least three genes account for familial papillary thyroid carcinoma: TCO and MNG1 excluded as susceptibility loci from a large Tasmanian family. 1042 54

We analyzed the pharmacological properties of 17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6b eta-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride (TRK-820) using Chinese hamster ovary (CHO) cells expressing cloned rat mu-, delta- and kappa-opioid receptors and human nociceptin receptor. TRK-820 showed high affinity for the kappa-opioid receptor, with a Ki value of 3.5 +/- 0.9 nM. In CHO cells expressing kappa-opioid receptors, TRK-820 inhibited forskolin-stimulated cAMP accumulation, and the maximal inhibitory effect was equivalent to that of (+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidiny l)-1-oxaspiro-(4,5)dec-8-yl]benzeneacetamide (U69,593), a full agonist of kappa-opioid receptor. In CHO cells expressing mu-opioid receptors, TRK-820 inhibited cAMP accumulation, but the maximal inhibitory effect was significantly smaller than that of [D-Ala2, N-MePhe4, Gly-ol5]enkephalin (DAMGO), a full agonist of mu-opioid receptor. In CHO cells expressing delta-opioid receptor, the inhibitory effect of TRK-820 on cAMP accumulation was very weak. Using site-directed mutagenesis, the high affinity of TRK-820 for the kappa-opioid receptor was revealed to require Glu297. TRK-820 bound to the nociceptin receptor with a Ki value of 380 +/- 50 nM. TRK-820 by itself had no effect on cAMP accumulation in CHO cells expressing nociceptin receptors, but significantly antagonized the nociceptin (10 nM)-mediated inhibition of cAMP accumulation at high concentrations. These results indicate that TRK-820 acts as a full agonist for the kappa-opioid receptor, a partial agonist for the mu-opioid receptor and a low-affinity antagonist for the nociceptin receptor.
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PMID:Pharmacological properties of TRK-820 on cloned mu-, delta- and kappa-opioid receptors and nociceptin receptor. 1044 Jan 1

Saccharomyces cerevisiae cells lacking the regulatory subunit of casein kinase 2 (CK-2), encoded by the gene CKB1, display a phenotype of hypersensitivity to Na(+) and Li(+) cations. The sensitivity of a strain lacking ckb1 is higher than that of a calcineurin mutant and similar to that of a strain lacking HAL3, the regulatory subunit of the Ppz1 protein phosphatase. Genetic analysis indicated that Ckb1 participates in regulatory pathways different from that of Ppz1 or calcineurin. Deletion of CKB1 increased the salt sensitivity of a strain lacking Ena1 ATPase, the major determinant for sodium efflux, suggesting that the function of the kinase is not mediated by Ena1. Consistently, ckb1 mutants did not show an altered cation efflux. The function of Ckb1 was independent of the TRK system, which is responsible for discrimination of potassium and sodium entry, and in the absence of the kinase regulatory subunit, the influx of sodium was essentially normal. Therefore, the salt sensitivity of a ckb1 mutant cannot be attributed to defects in the fluxes of sodium. In fact, in these cells, both the intracellular content and the cytoplasm/vacuole ratio for sodium were similar to those features of wild-type cells. The possible causes for the salt sensitivity phenotype of casein kinase mutants are discussed in the light of these findings.
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PMID:Biochemical and genetic analyses of the role of yeast casein kinase 2 in salt tolerance. 1051 37

Point mutations affecting the NTRK1/TRKA gene, encoding one of the receptors for the nerve growth factor (NGF), have been detected in congenital insensitivity to pain with anhidrosis (CIPA), a human hereditary sensory neuropathy characterized by absence of reaction to noxious stimuli and anhidrosis. To define the defect of NTRK1 in CIPA patients, we have introduced one of the previously reported mutations (Gly571Arg) into both the NTRK1 and the TRK-T3 oncogene cDNAs. The expression of the mutated constructs into COS1 cells revealed that the introduced mutation, while not affecting its correct membrane localization, rendered the NTRK1 protein unable to undergo activation upon stimulation with NGF. Similarly, the mutation abolished the constitutive activation of the TRK-T3 oncogene. Transfection into NIH3T3 and PC12 cells showed the loss of transforming and differentiating activity by the mutated constructs. Our results demonstrate clearly that the CIPA mutations cause the inactivation of the NTRK1 receptor, thus exerting a loss of function effect, and provide an experimental approach to distinguish functional mutations from genetic polymorphisms.
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PMID:The Gly571Arg mutation, associated with the autonomic and sensory disorder congenital insensitivity to pain with anhidrosis, causes the inactivation of the NTRK1/nerve growth factor receptor. 1056 24

TRK-820, a new type of 4,5-epoxymorphinan derivative, was investigated in vivo for antinociceptive activities and its selectivity on various opioid receptors in mice. TRK-820 given s.c. or p.o. was found to be 351- and 796-fold more potent than U50,488H with acetic acid-induced abdominal constriction test. The duration of the antinociceptive effect produced by TRK-820 was longer than that produced by mu-opioid receptor agonist morphine or other kappa-opioid receptor agonists. In addition, with four other antinociceptive assays, low temperature hot plate (51 degrees C), thermal tail flick, mechanical tail pressure and tail pinch tests, TRK-820 was also found to be 68- to 328-fold more potent than U-50488H, and 41- to 349-fold more potent than morphine in producing antinociception, as comparing the weight of the different compound. However, TRK-820 was less active in inhibiting the high temperature (55 degrees C) hot plate response. The antinociceptive effects produced by TRK-820 were inhibited by nor-BNI, but not by naloxone or naltrindole (NTI) with the abdominal constriction test, indicating that the antinociception is selectively mediated by the stimulation of kappa-, but not mu- or delta-opioid receptors. Co-administration of TRK-820 with morphine slightly enhanced the antinociception induced by morphine in the mouse hot plate test. On the other hand, pentazocine significantly reduced the morphine-induced antinociception. TRK-820 produced sedation at doses, which are much higher than the doses for producing antinociception. These results indicate that the potent antinociception induced by TRK-820 is mediated via the stimulation of kappa-, but not mu- or delta-opiod receptors.
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PMID:Potent antinociceptive effects of TRK-820, a novel kappa-opioid receptor agonist. 1057 86

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

Rearrangements of NTRK1 proto-oncogene were detected in 'spontaneous' papillary thyroid carcinomas with a frequency varying from 5 to 25% in different studies. These rearrangements result in the formation of chimaeric genes composed of the tyrosine kinase domain of NTRK1 fused to 5' sequences of different genes. To investigate if the NTRK1 gene plays a role in radiation-induced thyroid carcinogenesis, we looked for the presence of NTRK1-activating rearrangements in 32 human thyroid tumours (16 follicular adenomas, 14 papillary carcinomas and two lymph-node metastases of papillary thyroid carcinomas) from patients who had received external radiation, using the reverse transcription polymerase chain reaction, Southern blot and direct sequencing techniques. These data were compared with those obtained in a series of 28 'spontaneous' benign and malignant thyroid tumours, collected from patients without a history of radiation exposure and four in vitro culture cell lines derived from 'spontaneous' thyroid cancers. Our results concerning the radiation-associated tumours showed that only rearrangements between NTRK1 and TPM3 genes (TRK oncogene) were detected in 2/14 papillary carcinomas and in one lymph-node metastasis of one of these papillary thyroid carcinomas. All the radiation-associated adenomas were negative. In the 'spontaneous' tumours, only one of the 14 papillary carcinomas and one of the four in vitro culture cell lines, derived from a papillary carcinoma, presented a NTRK1 rearrangement also with the TPM3 gene. Twenty-five of this series of radiation-associated tumours were previously studied for the ras and RET/PTC oncogenes. In conclusion, our data: (a) show that the overall frequency of NTRK1 rearrangements is similar between radiation-associated (2/31: 6%) and 'spontaneous' epithelial thyroid tumours (2/32: 6%). The frequency, if we consider exclusively the papillary carcinomas, is in both cases 12%; (b) show that the TRK oncogene plays a role in the development of a minority of radiation-associated papillary thyroid carcinomas but not in adenomas; and (c) confirm that RET/PTC rearrangements are the major genetic alteration associated with ionizing radiation-induced thyroid tumorigenesis.
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PMID:Search for NTRK1 proto-oncogene rearrangements in human thyroid tumours originated after therapeutic radiation. 1064 82

We have already reported that TRK-820, (-)-17-cyclopropylmethyl-3, 14b-dihydroxy-4, 5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride, a new selective kappa-opioid receptor agonist, has affinity for kappa-subtype opioid receptors other than the kappa(1)-opioid receptor. It would be of interest to examine whether the different kappa-opioid receptor subtype properties of TRK-820 participate in its antinociceptive action in the inflamed paw test and the formalin test. TRK-820 produced a potent antinociceptive effect, which was inhibited by the selective kappa-opioid receptor antagonist nor-binaltorphimine, but not by the mu-opioid receptor antagonist naloxone in the mechanical paw pressure test. TRK-820 also produced a potent antinociceptive effect in rats with adjuvant-induced arthritis. TRK-820 and morphine, a prototype mu-opioid receptor agonist, were equally effective in inhibiting the nociceptive responses in the arthritic rats and in the normal rats, while ICI-199441, 2-(3, 4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]- acetamide, a kappa-opioid receptor agonist, was about 5-fold less potent in the arthritic rats than in the normal rats. In the formalin test TRK-820 had a very similar antinociceptive potency to that of ICI-199441, unlike in the arthritic rats in which TRK-820 was 2.5 times more potent than ICI-199441. It is concluded that TRK-820 produced a potent antinociceptive action via the stimulation of kappa-opioid receptors in rats. TRK-820 has a unique antinociceptive profile different from that of the other kappa-opioid receptor agonists such as ICI-199441 in arthritic rats.
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PMID:Characterization of the antinociceptive effects of TRK-820 in the rat. 1065 Jan 53

Receptor tyrosine kinases often have critical roles in particular cell lineages by initiating signalling cascades in those lineages. Examples include the neural-specific TRK receptors, the VEGF and angiopoietin endothelial-specific receptors, and the muscle-specific MUSK receptor. Many lineage-restricted receptor tyrosine kinases were initially identified as 'orphans' homologous to known receptors, and only subsequently used to identify their unknown growth factors. Some receptor-tyrosine-kinase-like orphans still lack identified ligands as well as biological roles. Here we characterize one such orphan, encoded by Ror2 (ref. 12). We report that disruption of mouse Ror2 leads to profound skeletal abnormalities, with essentially all endochondrally derived bones foreshortened or misshapen, albeit to differing degrees. Further, we find that Ror2 is selectively expressed in the chondrocytes of all developing cartilage anlagen, where it essential during initial growth and patterning, as well as subsequently in the proliferating chondrocytes of mature growth plates, where it is required for normal expansion. Thus, Ror2 encodes a receptor-like tyrosine kinase that is selectively expressed in, and particularly important for, the chondrocyte lineage.
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PMID:Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development. 1070 Jan 81


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