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)

The beta-catenin pathway has been conclusively demonstrated to regulate differentiation and patterning in multiple model systems. In thyroid cancer, alterations are often seen in proteins that regulate beta-catenin, including those of the RAS, PI3K/AKT, and peroxisome proliferation activated receptor-gamma (PPARgamma) pathways, and evidence from the literature suggests that beta-catenin may play a direct role in the dedifferentiation commonly observed in late-stage disease. RET/PTC rearrangements are frequent in thyroid cancer and appear to be exclusive from mutational events in RAS and BRAF. Activation of AKT by phosphatidylinositide-3 kinase (PI3K), a RAS effector, results in GSK3beta phosphorylation and deactivation and subsequent beta-catenin upregulation in thyroid cancer. Activating mutations in beta-catenin, which have been demonstrated in late-stage thyroid tumors, correlate with beta-catenin nuclear localization and poor prognosis. We hypothesize that activation of the RAS, PI3K/AKT, and PPARgamma pathways ultimately impinges upon beta-catenin. We further propose that if mutations in BRAF, RAS, and RET/PTC rearrangements are mutually exclusive in certain thyroid tumors or tumor types, as has already been shown for papillary thyroid cancer, then these interconnected pathways may cooperate in the initiation and promotion of the disease. We believe that clinical benefit for thyroid cancer patients could be derived from disrupting the middle or distal pathway effectors of these pathways, such as AKT or beta-catenin.
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PMID:Multiple signaling pathways converge on beta-catenin in thyroid cancer. 1602 21

Knowledge of the molecular events that govern human thyroid tumorigenesis has grown considerably in the past ten years. Key genetic alterations and new oncogenic pathways have been identified. Molecular genetic aberrations in thyroid carcinomas bear noteworthy resemblance to those in acute myelogenous leukemias. Thyroid carcinomas and myeloid leukemias both possess transcription factor gene rearrangements-PPARgamma-related translocations in thyroid carcinoma and RARalpha-related and CBF-related translocations (amongst others) in myeloid leukemia. PPARgamma and RARalpha are closely related members ofthe same nuclear receptor subfamily, and the PML-RARalpha and PAX8-PPARgamma fusion proteins both function as dominant negative inhibitors of their wild-type parent proteins. Thyroid carcinomas and myeloid leukemias also both harbor NRAS mutations (15-25% of both cancers) and receptor tyrosine kinase mutations--RET mutations in thyroid carcinomas and FLT3 mutations in myeloid leukemias. The NRAS and tyrosine receptor kinase mutations are not observed in the same thyroid carcinoma or leukemia patients, suggesting that multiple initiating pathways exist in both. Lastly, thyroid carcinomas and myeloid leukemias possess p53 mutations at relatively low frequency (10-15%) in patients who tend to be older and have more aggressive, therapy resistant disease. Such parallels are unlikely to occur by chance alone and argue that common mechanisms underlie these diverse epithelial and hematologic cancers. The comparison of thyroid carcinomas and myeloid leukemias may highlight areas of thyroid cancer investigation worthy of further focus. For example, few collaborating mutations have been defined in thyroid carcinomas even though they play a clear role in myeloid leukemias, as exemplified by RARalpha rearrangements and FLT3 mutations that together dictate the promyleocytic leukemia phenotype. Functional interactions between collaborating mutations are possible at multiple levels, and it is tempting to speculate that some thyroid carcinomas might develop through an unique combination or co-activation of RET and RAS and/or RET and PPARgamma (and/or other) signaling systems. In fact, the ELE1-RET (PTC3) fusion protein contains the ELE1 nuclear receptor co-activator domain and it appears to physically associate with and inhibit wild-type PPARgamma in some papillary carcinomas. The similarities of the fusion proteins in thyroid carcinoma and myeloid leukemia suggest that a more directed search for fusion genes in non-thyroid carcinomas is warranted. In fact, novel fusion genes have been identified recently in aggressive midline, secretory breast, and renal cell carcinomas, although the epithelial nature of the latter is not well-documented. Interestingly, these cancers all tend to present more frequently in adolescence and young adulthood in a manner similar to thyroid and myeloid malignancies that have fusion genes. The analyses of cancers that present earlier in life may enhance fusion gene recognition in other carcinoma types. Definition and biologic characterization of the precursor cells that give rise to thyroid carcinoma will also be important. Myeloid leukemias are thought to arise from stem/progenitor cells that acquire disturbed self-renewal and differentiation capacities but retain characteristics of the myeloid lineages. Although the presence of comparable stem/progenitor cells in the thyroid are not defined, distinct thyroid cancer lineages and patterns of differentiation exist and candidate stem/progenitor cells such as the p63-immunoreactive solid cell nests are apparent. A last important area is development of molecular-based therapies for thyroid carcinoma patients resistant to standard radio-iodine treatment. Treatments for such cancers are limited and pathways defined by thyroid cancer mutations are prime targets for pharmacologic interventions with molecular inhibitors. Tyrosine kinase inhibitors and nuclear receptor ligands have proven dramatically effective in some myeloid leukemia patients. Various molecular inhibitors are being investigated now in thyroid cancer models. Such developments predict that the thyroid cancer model will continue to provide biologic insights into human carcinoma biology and that improved pathologic diagnosis and treatment for thyroid cancer patients sit on the not too distant horizon.
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PMID:Molecular events in follicular thyroid tumors. 1620 39

The efficient and specific introduction of genes into cancer cells in vivo remains a major challenge for current gene therapy modalities. Peptides possess appropriate properties to serve as tumor-targeting agents. Thus, finding new cancer-selective peptides directing gene transfer to neoplastic cells by reducing transduction of normal cells is a central goal for molecular targeting. We have previously reported identification of a peptide (HTFEPGV) that selectively binds to human medullary thyroid carcinoma (MTC)-derived TT cells in vitro and transplanted tumor xenografts in vivo, using phage display. In the present study, we have performed this approach in primary orthotopically growing murine MTCs of RET-C634R transgenic mice as a clinically relevant model for thyroid cancer by intravenous injection of a complex peptide library. Two rounds of screening on primary tumors yielded multiple copies of a phage that displays a cyclic 7-amino acid peptide, SRESPHP, with a 3000-fold increase in titer between rounds 1 and 2. The selected phage showed highly specific binding to the tumor after systemic administration, whereas binding to other organs such as lung, liver, kidney, and heart was reduced up to 90%. After tail vein injection, homing to the tumor was substantially reduced in the presence of synthetic SRESPHP peptide, indicating that tumor phage interaction strictly depends on the displayed peptide. Immunohistochemical analysis of paraffin sections from mouse tissues revealed direct binding of the SRESPHP peptide to MTC tissue. Moreover, this peptide also mediates binding to human MTC cells in vitro and in vivo, suggesting abundant expression of its cognate receptor in murine and human medullary thyroid carcinoma. Because the SRESPHP peptide is also efficiently internalized into MTC cells, it likely provides the basis for a new selective therapy of medullary thyroid carcinoma.
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PMID:Novel SRESPHP peptide mediates specific binding to primary medullary thyroid carcinoma after systemic injection. 1625 60

Early diagnosis for thyroid carcinoma, potentially before neoplastic transformation has taken place, would allow preventive and thus curative surgical intervention. Identifying and characterizing the RET proto-oncogene as the disease-causing gene for hereditary medullary thyroid carcinoma and then establishing a genotype-phenotype correlation served as the prerequisite for the risk-adapted prophylactic surgical approach practised today. Carriers of RET mutations associated with very aggressive tumour behaviour should be subjected to prophylactic thyroidectomy within the 1st year of life. For individuals harbouring less virulent types of mutations, prophylactic intervention is recommended at 5-20 years. Although genetic research on hereditary nonmedullary thyroid cancer is still in progress, initial results indicate the need of prophylactic surgical treatment also for this subgroup of thyroid neoplasia.
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PMID:[Prophylactic thyroid surgery]. 1632 97

Recurrent chromosomal rearrangements are common in cancer cells and may be influenced by nonrandom positioning of recombination-prone genetic loci in the nucleus. However, the mechanism responsible for spatial proximity of specific loci is unknown. In this study, we use an 18 Mb region on 10q11.2-21 containing the RET gene and its recombination partners, the H4 and NCOA4 (ELE1) genes, as a model chromosomal region frequently involved in RET/PTC rearrangements in thyroid cancer. RET/PTC is particularly common in tumors from children exposed to ionizing radiation. Using fluorescence in situ hybridization and three-dimensional microscopy, the locations of five different loci in this region were mapped in interphase nuclei of normal human thyroid cells. We show that RET and NCOA4 are much closer to each other than expected based on their genomic separation. Modeling of chromosome folding in this region suggests the presence of chromosome coiling with coils of approximately 8 Mb in length, which positions the RET gene close to both, the NCOA4 and H4, loci. There was no significant variation in gene proximity between adult and pediatric thyroid cells. This study provides evidence for large-scale chromosome folding of the 10q11.2-21 region that offers a structural basis for nonrandom positioning and spatial proximity of potentially recombinogenic intrachromosomal loci.
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PMID:Interphase chromosome folding determines spatial proximity of genes participating in carcinogenic RET/PTC rearrangements. 1633 Dec 64

Radiation exposure at a young age is the only environmental factor known to cause thyroid cancer, predominantly of the papillary type. We have previously reported a high percentage (86.7%) of RET-positive papillary thyroid cancers in a cohort of individuals exposed to external radiation of the head and neck area before the age of 16. Recently, we and others have reported that point mutations of the BRAF gene occur with high frequency among sporadic adult papillary thyroid carcinomas, but occur at a much lower frequency in the population exposed after the Chernobyl accident. We here report that there is a similar low frequency of BRAF mutations among our cohort of those exposed to external beam radiation as children who later developed papillary thyroid cancer as adults. Samples were analyzed by mutation allele-specific amplification (MASA) for the most common T1799A mutation in exon 15 that converts amino acid 600 from valine to glutamate. In 23 cases, only 1 sample was positive. These results are further evidence that BRAF mutations, while common in sporadic adult papillary thyroid cancers, are rare events in cancers seen in subjects exposed to radiation as children.
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PMID:Low frequency of BRAF mutations in adult patients with papillary thyroid cancers following childhood radiation exposure. 1648 15

RET (rearranged during transfection) is a transmembrane tyrosine kinase and acts as co-receptor of glial-derived neurotrophic factor (GDNF) family neurothrofic factors in complex with GFRalpha family proteins; RET is important for development of enteric nervous system and renal organogenesis during embryonal life. Alterations in Ret gene are related to several neoplasias: point mutations are identified in medullary thyroid carcinoma (MTC) and multiple endocrine neoplasias 2A and B (MEN2A and B), while translocations and chromosomal inversions cause papillary thyroid carcinoma (PTC). We expressed recombinant RET kinase domain (rRET) containing the active site, the ATP binding pocket, and the activation loop with regulatory activity, with the Baculovirus expression system. RET was purified by a two-step procedure consisting of an anion exchange chromatography followed by nickel affinity chromatography. Moreover a biochemical characterization of the recombinant product was performed in order to verify its activity (by ELISA) and physical state (dynamic light scattering). We used rRET to validate an ELISA-based kinase assay, by testing inhibitors reported in literature such as PP1 and PP2. This method represents an easy system to screen potential inhibitors found by computational methods. We also produced V804M mutants to identify inhibitors that can overcome resistance to PP1 and ZD6474. The catalytic domain of RET can be used also for X-ray diffraction to obtain information about the three-dimensional structure, necessary for a rational design of selective inhibitors: it represents an important tool to understand the molecular mechanisms causing thyroid cancer and to care it.
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PMID:A rapid method for the purification of wild-type and V804M mutant ret catalytic domain: A tool to study thyroid cancer. 1649 Feb 47

Thyroid cancer is one of the few malignancies that are increasing in incidence. Recent advances have improved our understanding of its pathogenesis; these include the identification of genetic alterations that activate a common effector pathway involving the RET-Ras-BRAF signalling cascade, and other unique chromosomal rearrangements. Some of these have been associated with radiation exposure as a pathogenetic mechanism. Defects in transcriptional and post-transcriptional regulation of adhesion molecules and cell-cycle control elements seem to affect tumour progression. This information can provide powerful ancillary diagnostic tools and can also be used to identify new therapeutic targets.
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PMID:Pathogenetic mechanisms in thyroid follicular-cell neoplasia. 1655 81

Gain-of-function mutations within the receptor tyrosine kinase gene RET cause inherited and non-inherited thyroid cancer. Somatic gene rearrangements of RET have been found in papillary thyroid carcinoma and germline point mutations in multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma (FMTC). Conversely, loss-of-function mutations are responsible for the development of Hirschsprung's disease, a congenital malformation of the enteric nervous system. Comparison between normal RET signaling activated by the RET ligand glial cell line-derived neurotrophic factor (GDNF) and abnormal RET signaling caused by various mutations has led to a deeper understanding of disease mechanisms. The focus of the present review is on recent progress in the study of RET signaling dysfunction in human diseases.
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PMID:RET receptor signaling: dysfunction in thyroid cancer and Hirschsprung's disease. 1663 61

Papillary thyroid carcinomas (PTCs) are associated with alterations in several proto-oncogenes related with nervous system development and function, such as TrkA and RET, which are commonly rearranged in these carcinomas. The other oncogenic event recently identified in PTC is the BRAF V600E mutation. Because the role of TrkA was not completely elucidated in thyroid cancer ethiopathogenesis, we decided to study the expression of active, phosphorylated TrkA and of its coreceptor p75 neurotrophin receptor (p75 NTR) in a series of 92 PTC (37 lesions of conventional PTC, 28 of follicular variant of PTC [FVPTC], and 27 of other variants of PTC) as well as in 21 samples of normal thyroid and nonneoplastic thyroid lesions used as a controls. We observed neoexpression of p75 NTR in PTC, particularly in conventional PTC and in other variants of PTC displaying a papillary growth pattern, rather than in FVPTC. No immunoexpression of p75 NTR was observed in normal thyroid nor in nonneoplastic thyroid lesions. The cellular localization of p75 NTR immunoexpression was also significantly associated with the growth pattern of PTC, being much more frequently detected in an apical localization in PTC with papillary architecture than in PTC with a follicular or solid growth pattern. This apical localization of p75 NTR was significantly associated with the presence of BRAF V600E. No significant differences were detected between normal thyroid, nonneoplastic lesions, and PTC (or any PTC variant) regarding expression/activation of TrkA, thus suggesting that by itself and in contrast to p75 NTR, TrkA is not altered during PTC development.
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PMID:The p75 neurotrophin receptor is widely expressed in conventional papillary thyroid carcinoma. 1664 54


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