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)

Although sporadic medullary thyroid carcinoma (MTC) tends to be unicentric and confined to one lobe, total thyroidectomy is usually performed because of the risk of a hereditary or bilateral process. Germline RET mutation analysis can discriminate hereditary MTC and truly sporadic, nonhereditary MTC. We analyzed 72 of 94 patients with MTC to establish the genetic nature and the clinical features of nonhereditary MTC. Since 1996 we have prospectively treated 15 patients with nonhereditary MTC (prospective study group, or PSG) according to a unilateral surgery policy. A group of 22 previously operated patients in whom the nonhereditary nature was established served as controls (retrospective study group, or RSG). Systematic central and ipsilateral neck dissection was performed in both groups. Outcome was assessed using postoperative stimulated serum calcitonin levels; a normal value was considered a biochemical cure. All 24 hereditary MTC patients carried germline RET mutations: 8 of 48 patients with apparently sporadic MTC had the mutations, and 6 of the 8 had bilateral MTC. All 40 patients without mutations had a unilateral tumor. In the RSG group 15 of 22 (68%) patients underwent total thyroidectomy, and the biochemical cure rate was 68%. Although only 3 of 15 (20%) of the PSG patients underwent total thyroidectomy, 12 of the 15 (80%) achieved biochemical cure. Univariate analyses revealed that pathologic node involvement- high T and N stages-was adversely related to biochemical cure. The extent of thyroid resection was not related to biochemical cure. Of 20 patients with node involvement, 10 achieved biochemical cure, indicating the importance of systematic neck dissection. Hemithyroidectomy with systematic central and ipsilateral neck dissection is appropriate surgery for nonhereditary MTC.
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PMID:Prospective trial of unilateral surgery for nonhereditary medullary thyroid carcinoma in patients without germline RET mutations. 1201 84

Preliminary results of treatment of inherited medullary thyroid carcinoma, diagnosed primarily with genetic analysis of mutation of protooncogene RET are presented. Among 16 carriers of mutation identical with mutation diagnosed earlier in proband, there were 4 patients with clinically obvious medullary thyroid carcinoma and 12 asymptomatic carriers. In all patients, in whom calcitonin level was increased preoperatively, its normalization was obtained. The paper summarizes these aspects of cooperation between geneticians and physicians in which diagnostic results influence clinical decisions (indication and time of thyroid and lymph nodes surgery and it's spectrum, range of diagnostic procedures towards pheochromocytoma and parathyroid hyperplasia in relation to the found mutation).
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PMID:[Consequences of clinical genetic analysis of RET proto-oncogene]. 1218 57

Medullary thyroid carcinoma (MTC) can be divided into two subgroups: sporadic or inherited. Hereditary form of MTC is often believed to be form with better prognosis than sporadic one. In this study the differences in MTC prognosis in Polish population of patients was analyzed. The group of 169 patients with MTC was examined. Hereditary cancer was stated in 48 (28%) patients. The median age of disease onset was 41 years (from 7 to 71 years). Genetic examination of RET protooncogene was performed in all patients. The calcitonin and CEA serum level analysis and radiological and radioisotopic examinations were used for monitoring of the disease course. Nineteen cases of MEN 2A syndrome, 11 cases of MEN 2B one and 18 cases of non classified familial MTC were recognized among patients with inherited MTC. Significantly lower age of disease onset in inherited MTC than in sporadic one was observed (27 years vs. 43.7 years, p < 0.001). Local or nodal recurrence was observed in 22 (13%) patients, distant metastases were stated in 21 (12%) patients. Basal or stimulated serum calcitonin level was increased in 85 (50%) patients. No significant differences between sporadic and inherited disease were observed. Eight patients died during observation, including 3 patients with sporadic MTC and 5 patients with inherited MTC. The updated 10-year survival rate was 97% in patients with sporadic MTC; in hereditary MTC it was about 20% worse. The complications related to the presence of adrenal tumors were the main reason for death in MEN2 and no significant differences in the course of MTC itself were observed.
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PMID:[Results of treating medullary thyroid carcinoma: the differences between sporadic and inherited forms]. 1218 60

Prophylactic thyroidectomy is recommended for carriers of RET protooncogene mutations owing to their nearly complete penetrance for medullary thyroid carcinoma (MTC). However, this guideline is challenged by mutations exhibiting variable penetrance of C-cell pathology. A 38-year-old woman presented with pathologic basal and pentagastrin-stimulated calcitonin levels. Genetic analysis revealed a heterozygous RET protooncogene germline mutation in codon 791 (exon 13) (TAT(Tyr)-->TTT(Phe)), followed by thyroidectomy and systematic central lymph node dissection. Histology showed C-cell hyperplasia (CCH) only. Three additional carriers were identified among family members. The 71-year-old father refused surgery despite pathologic calcitonin levels. The index patient's 37-year-old sister had normal basal and stimulated calcitonin levels, and her 6-year-old son had a 10-fold rise of calcitonin after pentagastrin stimulation. Both patients underwent the same operation as the index patient. The sister had 25 hyperplastic C-cells, but the her son had extensive CCH without MTC. The eldest uncle of the index patient had died of metastatic MTC at the age of 52 with unknown carrier status. Despite variable penetrance, each carrier of a RET protooncogene germline mutation should undergo thyroidectomy, even if basal and stimulated calcitonin levels are normal because at present no test can exclude or predict the age of development of MTC. Moreover, pathologic calcitonin levels cannot differentiate between CCH and MTC. Central lymph node dissection is recommended, as lymph node metastases occur early, significantly worsening the prognosis.
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PMID:Surgical strategy in a kindred with a rare RET protooncogene mutation of variable penetrance with regard to multiple endocrine neoplasia. 1220 48

Interleukin 1 beta (IL-1 beta) is a proinflammatory cytokine that maintains thermal hyperalgesia and facilitates the release of calcitonin gene-related peptide from rat cutaneous nociceptors in vivo and in vitro. Brief applications of IL-1 beta to nociceptive neurons yielded a potentiation of heat-activated inward currents (Iheat) and a shift of activation threshold toward lower temperature without altering intracellular calcium levels. The IL-1 beta-induced heat sensitization was not dependent on G-protein-coupled receptors but was mediated by activation of protein kinases. The nonspecific protein kinase inhibitor staurosporine, the specific protein kinase C inhibitor bisindolylmaleimide BIM1, and the protein tyrosine kinase inhibitor genistein reduced the sensitizing effect of IL-1 beta whereas negative controls were ineffective. RT-PCR and in situ hybridization revealed IL-1RI but not RII expression in neurons rather than surrounding satellite cells in rat dorsal root ganglia. IL-1 beta acts on sensory neurons to increase their susceptibility for noxious heat via an IL-1RI/PTK/PKC-dependent mechanism.
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PMID:IL-1 beta potentiates heat-activated currents in rat sensory neurons: involvement of IL-1RI, tyrosine kinase, and protein kinase C. 1237 72

From collagenase digests of human thyroid, endothelial cells were separated from follicular cells by their greater adherence to gelatin-coated plates. Endothelial cells were further purified using fluorescence-activated cell sorting, selecting for cells expressing factor VIII-related antigen. Isolated cells were negative for thyroglobulin and calcitonin when examined by immunostaining. The receptor for the angiopoietins, Tie-2, was expressed by the cells, and expression was increased by agents that elevate cAMP. Nitric oxide synthase (NOS) 3, the endothelial form of NOS, was expressed by the cells and similarly regulated. Cells responded strongly to the mitogen fibroblast growth factor (FGF)-2 in growth assays but only weakly to vascular endothelial growth factor (VEGF). VEGF was, however, able to stimulate nitric oxide release from the cells consistent with their endothelial origin. The FGF receptor (FGFR1) was full length (120 kDa) and immunolocalized to the cytosol and nucleus. Thyrotropin (TSH) did not regulate FGFR1, but its expression was increased by VEGF. Thrombospondin, a product of follicular cells, was a growth inhibitor, but neither TSH nor 3,5,3'-triiodothyronine had direct mitogenic effects. Thyroid follicular cell conditioned medium contained plasminogen activator activity and stimulated the growth of the endothelial cells, but when treated with plasminogen to produce the endothelial-specific inhibitor, angiostatin, growth was inhibited. Human thyroid endothelial cell cultures will be invaluable in determining the cross talk between endothelial and follicular cells during goitrogenesis.
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PMID:Isolation and characterization of human thyroid endothelial cells. 1962 78

Since 1969 to 2000 twenty one patients from 16 families with syndrome of multiple endocrine neoplasia (MEN) type 2 were examined. Medullary cancer of the thyroid gland (MCTG) was diagnosed in 18 patients, pheochromocytoma--in 15 (in 13 of them--two-sided), primary hyperparathyroidism--in 2. In 9 patients from 5 families syndrome MEN 2 was confirmed genetically (mutation in codon 634 of 11th exon RET in 7 patients with MEN 2a and in codon 918 in 2 patients with MEN 2b). None of the patients had extraadrenal pheochromocytoma, in 9 (60%) patients multicentric tumors within one adrenal gland were diagnosed. All the 18 patients with MCTG underwent extrafascial thyroidectomy with removal of fat and lymph nodes of paratracheal zone, 9 patients--one-sided (6) or two-sided (3) removal of fat and lymph nodes of lateral triangle of neck. Prophylactic thyreoidectomy was performed in 11-year old patient with genetically verified MEN 2a and without topical data of MCTG, 2 patients of 3 and 19 years of age with genetically verified MEN 2 are to undergo prophylactic thyroidectomy. Prophylactic thyroidectomy is necessary in the presence of genetic disorders in members of families with MEN 2 despite absence of structural changes in thyroid gland. Level of basal and stimulated calcitonin may be used as marker of recurrence or metastatic growth only. In MEN 2 after organ-saving operation rate of true recurrence of tumor is high because of genetic damage of medullary layer of adrenal gland.
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PMID:[Diagnosis and treatment of syndrome of multiple endocrine neoplasia type 2]. 1241 13

Chronic constriction of the sciatic nerve, leading to a hyperalgesic state, results in a partial lesion wherein some axons are injured and others remain intact. Here we sought to characterize reactive changes which occur in DRG cell bodies of injured and uninjured axons projecting to skin and muscle. Using immunohistochemistry combined with flurorogold and fluororuby retrograde labelling to define DRG cell bodies associated with injured and uninjured axons, we analysed the DRG immunoreactivity (IR) for tumour necrosis factor-alpha (TNF), interleukin-10 (IL-10), the sensory neuron-specific channel vanilloid receptor 1 (VR1), isolectin B4 (IB4) and calcitonin-gene-related peptide (CGRP) 4 days after a unilateral chronic constriction injury (CCI) of the rat sciatic nerve. TNF IR was predominantly localized in neuronal DRG cells. In DRG with an intact nerve, TNF IR was present in 45%, IL-10 IR in 46%, VR1 IR in 44%, IB4 IR in 51% and CGRP IR in 40% of all neuronal profiles. Four days after CCI, TNF IR was increased in medium-sized neurons, whereas IR for IL-10, VR1 and IB4, predominantly present in small neurons, was reduced. Importantly, not only injured but also adjacent spared neurons contributed markedly to increased TNF IR. Neurons projecting to both muscle and skin displayed upregulated TNF IR after CCI. TNF in medium-sized neurons colocalized with neurofilament and trkB, but not with IB4, trkA or RET, suggesting a selective phenotypic switch in presumably low-threshold myelinated primary afferents. Spared myelinated fibres with intact sensory functions but upregulated TNF expression may contribute to behavioural changes observed after nerve injury.
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PMID:Selective increase of tumour necrosis factor-alpha in injured and spared myelinated primary afferents after chronic constrictive injury of rat sciatic nerve. 1260 69

Adrenomedullin is a potent vasodilator peptide secreted by vascular endothelial and smooth muscle cells. Adrenomedullin stimulates the proliferation of quiescent rat vascular smooth muscle cells (VSMCs) via p42/p44 ERK/MAP kinase activation. Recently, receptor-activity-modifying proteins (RAMPs) have been shown to transport calcitonin-receptor-like-receptor (CRLR) to the cell surface to present either as CGRP receptor or adrenomedullin receptor. We investigated whether adrenomedullin acts as an autocrine/paracrine growth factor for cultured rat VSMCs and whether coexpressions of RAMP isoform and CRLR may mediate p42/p44 ERK/MAP kinase activation by adrenomedullin. Adrenomedullin dose-dependently stimulated the proliferation of quiescent rat VSMCs, and this effect was inhibited by an adrenomedullin receptor antagonist, a MAP kinase kinase inhibitor and phosphatidylinositol 3-kinase inhibitors. Addition of either CGRP(8-37) or anti-adrenomedullin antibody to exponentially growing rat VSMCs inhibited the serum-induced cell proliferation, suggesting its role as an autocrine/paracrine growth factor. Cotransfection of RAMP2 or RAMP3 with CRLR into rat VSMCs potentiated activation of cAMP activity, but not of p42/p44 ERK/MAP kinase activity in response to adrenomedullin. Our results suggest that adrenomedullin is an autocrine/paracrine growth factor for rat VSMCs via p42/p44 ERK/MAP kinase and phosphatidylinositol 3-kinase pathways and that it is not mediated by human RAMP-CRLR receptors.
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PMID:Adrenomedullin is an autocrine/paracrine growth factor for rat vascular smooth muscle cells. 1266 39

Medullary thyroid carcinoma (MTC) is a malignant tumor of the calcitonin-secreting parafollicular C cells of the thyroid occurring sporadically and as a component of the multiple endocrine neoplasia type 2/familial medullary thyroid carcinoma syndrome. The primary genetic cause of multiple endocrine neoplasia type 2 is germline mutation of the RET protooncogene. Somatic point mutations in RET also occur in sporadic MTC. Although RET mutation is likely sufficient to cause C-cell hyperplasia, the precursor lesion to MTC, tumor progression is thought to be due to clonal expansion caused by the accumulation of somatic events. Using the genome-scanning technique comparative genomic hybridization, we identified chromosomal imbalances that occur in MTC including deletions of chromosomes 1p, 3q26.3-q27, 4, 9q13-q22, 13q, and 22q and amplifications of chromosome 19. These regions house known tumor suppressor genes as well as genes encoding subunits of the multicomponent complex of glycosylphosphatidylinositol-linked proteins (glial cell line-derived neurotrophic factor family receptors alpha-2-4) and their ligands glial cell line-derived neurotrophic factor, neurturin, persephin, and artemin that facilitate RET dimerization and downstream signaling. Chromosomal imbalances in the MTC cell line TT were largely identical to those identified in primary MTC tumors, consolidating its use as a model for studying MTC.
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PMID:Genome-wide copy number imbalances identified in familial and sporadic medullary thyroid carcinoma. 1267 85


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