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)

Mutations to the RET proto-oncogene occur in as many as one in three cases of thyroid cancer and have been detected in both the medullary (MTC) and the papillary (PTC) forms of the disease. Of the nearly 400 chromosomal rearrangements resulting in oncogenic fusion proteins that have been identified to date, the rearrangements that give rise to RET fusion oncogenes in PTC remain the paradigm for chimeric oncoprotein involvement in solid tumors. RET-associated PTC tumors are phenotypically indolent and relatively less aggressive than RET-related MTCs. The mechanism(s) contributing to the differences in oncogenicity of RET-related MTC and PTC remains unexplained. Here, through cellular and molecular characterization of the two most common RET/PTC rearrangements (PTC1 and PTC3), we show that RET/PTC oncoproteins are highly oncogenic when overexpressed, with the ability to increase cell proliferation and transformation. Further, RET/PTCs activate similar downstream signaling cascades to wild-type RET, although at different levels, and are relatively more stable as they avoid lysosomal degradation. Absolute quantitation of transcript levels of RET, CCDC6, and NCOA4 (the 5' fusion genes involved in PTC1 and PTC3, respectively) suggest that these rearrangements result in lower RET expression in PTCs relative to MTCs. Together, our findings suggest PTC1 and PTC3 are highly oncogenic proteins when overexpressed, but result in indolent disease compared with RET-related MTCs due to their relatively low expression from the NCOA4 and CCDC6 promoters in vivo.
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PMID:Transcript level modulates the inherent oncogenicity of RET/PTC oncoproteins. 1948 96

Medullary thyroid cancer( MTC) is a neuroendocrine tumor arising from neural-crest-derived, calcitonin-secreting parafollicular C cells within the thyroid. Serum calcitonin (CT) is the most specific and sensitive marker for MTC for both the primary diagnosis and postsurgical follow-up. MTC may occur either sporadically or as part of a hereditary disease such as multiple endocrine neoplasia Type 2A (MEN 2A), multiple endocrine neoplasia Type 2B (MEN 2B) or familial medullary thyroid cancer(FMTC). The primary treatment of MTC is surgical removal of all neoplastic tissue present in the neck and lymph nodes; this should be performed after the careful exclusion of a phenochromocytoma. Mutations in the RET gene are associated with MEN2A, MEN2B and FMTC. Specific RET mutations are associated with each of the MEN2 syndromes and with the aggressiveness of MTC. Consequently, the nature of the RET mutation should guide major management decisions and inform the treatment strategy for MTC.
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PMID:[The treatment of medullary thyroid cancer]. 1983 21

The RET (rearranged during transfection) protooncogene encodes a single pass transmembrane receptor that is expressed in cells derived from the neural crest and the urogenital tract. As part of a cell-surface complex, RET binds glial derived neurotrophic factor (GDNF) ligands in conjunction with GDNF-family alpha co-receptors (GFRalpha). Ligand-induced activation induces dimerization and tyrosine phosphorylation of the RET receptor with downstream activation of several signal transduction pathways. Activating germline RET mutations play a central role in the development of the multiple endocrine neoplasia (MEN) syndromes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC) and also in the development of the congenital abnormality Hirschsprung's disease. Approximately 50% of patients with sporadic MTC have somatic RET mutations, and a significant portion of papillary thyroid carcinomas result from chromosomal inversions or translocations, which activate RET (RET/PTC oncogenes). The RET protooncogene has a significant place in cancer prevention and treatment. Timely thyroidectomy in kindred members who have inherited a mutated RET allele, characteristic of MEN2A, MEN2B, or FMTC, can prevent MTC, the most common cause of death in these syndromes. Also, recently developed molecular therapeutics that target the RET pathway have shown activity in clinical trials of patients with advanced MTC, a disease for which there has been no effective therapy.
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PMID:Targeting the RET pathway in thyroid cancer. 1993 98

Beta-catenin is involved in cell adhesion through catenin-cadherin complexes and as a transcriptional regulator in the Wnt signaling pathway. Its deregulation is important in the genesis of a number of human malignancies, particularly colorectal cancer. A range of studies has been undertaken in breast cancer, with contradictory associations reported among beta-catenin expression, clinicopathologic variables, and disease outcome. We undertook an immunohistochemical study measuring the levels and subcellular localization of beta-catenin in 292 invasive ductal breast cancers with known treatment and outcome. No association with breast cancer-specific death was observed for cytoplasmic or membrane expression alone; however, a continuous score representing both locations (membrane minus cytoplasmic expression: MTC score) was associated with a worse outcome in univariate analysis (P = 0.004), and approached significance in a multivariate analysis model that included lymph node, progesterone receptor (PR), and HER2 status (P = 0.054). Therefore, the MTC score was used for further statistical analyses due to the importance of both the subcellular location and the levels of expression of beta-catenin. An association was identified between high cytoplasmic expression (low MTC score), and high tumor grade (P = 0.004), positive Ki67 (P = 0.005), negative estrogen receptor (ER) (P = 0.005), positive HER2 (P = 0.04) status, and an active phosphoinositide 3-kinase pathway (P = 0.005), measured as PIK3CA mutations (P = 0.05) or PTEN loss (P = 0.05). Low cytoplasmic expression (high MTC score) was associated with the luminal A subtype (P = 0.004). In conclusion, a low beta-catenin MTC score is associated with an adverse outcome in breast cancer, which may be of mechanistic significance in the disease process.
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PMID:Cytoplasmic localization of beta-catenin is a marker of poor outcome in breast cancer patients. 2005 51

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome caused by missense gain-of-function mutations of the RET proto-oncogene. Three distinct clinical subtypes of MEN 2 have been characterized: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). The specific RET mutation may suggest a predilection toward a particular phenotype and clinical course, with strong genotype-phenotype correlations. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on classification of RET mutations into risk levels according to genotype-phenotype correlations. The excellent prognosis for MTC diagnosed at its earliest stage underscores the importance of prospective screening (calcitonin screening) for sporadic MTC and early diagnosis by RET-mutation analysis for hereditary MTC. MEN 2 provides a unique model for early prevention and cure of cancer and for the roles of stratified mutation-based diagnosis and therapy of carriers.
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PMID:Molecular genetics and phenomics of RET mutations: Impact on prognosis of MTC. 2008 56

Familial medullary thyroid carcinoma (FMTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. An identifiable RET mutation can be detected in about 85% of FMTC families. The majority of germline mutations in FMTC have been found in exons 10 and 11 of the RET proto-oncogene, specifically within the cysteine codons 609, 611, 618, 620, and 634. We screened members of a large Korean family that had a history of FMTC by genetic analyses, and propose a therapeutic approach for managing the disorder. We report a RET mutation in exon10, codon 618 that causes substitution of a cysteine by a serine in the cysteine-rich domain of the RET receptor in a three-generation FMTC family composed of 30 members with 11 carriers. Nine of the gene carriers were clinically affected. The FMTC with cysteine RET mutations found in the Korean population is consistent with the clinical pattern reported worldwide; to date there have been no ethnic differences identified for FMTC. Our results suggest that this genetic profile might be associated with usually aggressive clinical course with regional lymph node metastasis but late onset of MTC.
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PMID:A Korean family of familial medullary thyroid cancer with Cys618Ser RET germline mutation. 2011 74

MTC is a rare neuroendocrine thyroid tumour accounting for 3% to 10% of all thyroid malignancies. It can occur in a sporadic and a hereditary clinical setting. Hereditary MTC may either occur alone (familial MTC, FMTC) or as part of multiple endocrine neoplasia (MEN) type 2A, or MEN 2B. These disorders are due to germline mutations in the RET (REarranged during Transfection) gene. In carriers of MEN 2B-associated RET mutations, prophylactic thyroidectomy is indicated before the first year of life. In the case of MEN 2A-associated germline RET mutations with a high-risk profile, total thyroidectomy is warranted before the age of 2 years and certainly before the age of 4 years. At that age the risk of invasive MTC and metastases is acceptably low. Depending on the type of RET mutation, thyroidectomy can take place at an older age in patients with a lower risk profile. In case of elevated basal or stimulated serum calcitonin, preventive surgery including total thyroidectomy and central compartment dissection should be performed regardless of age. When MTC presents as a palpable tumour, total thyroidectomy should be combined with extensive lymph node dissection of levels II-V on both sides and level VI to prevent locoregional recurrences.
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PMID:An introduction to managing medullary thyroid cancer. 2022 15

Multiple endocrine neoplasia (MEN) 2a consists on medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. The identification of the RET proto-oncogene in 1993 has changed the prognosis of the disease. We have retrospectively studied the patients diagnosed of MEN 2a in our centre for the last 7 years in order to establish the most adequate age to undergo surgery. We present ten patients diagnosed with MEN 2a, whose ages ranged from 1.5 to 11 years old. Mean age at time of operation: 6,4 years An ultrasound study, calcitonin determinations and cathecholamines and urinary metanephrine levels were obtained before surgery. The surgical treatment is based on total total thyroidectomy, in selected cases lymph node resection in the central zone lf the neck. The most frequent RET mutation is the one affecting codon 634 (exon 10), which was found in children. Both of them had an alteration in codon 611 (exon11). No complications appeared after surgery and hospital discharge took place in the 2nd-4th day after surgery. Pathological findings were medullary thyroid microcarcinoma (MTMC) in 3 out of 10 patients, calcitonin preoperative tests were high in one of them. No tumoral cells were found in the lymph nodes. During the follow up period, 9 out of 10 from the operated patients, maintained normal calcitonin, CEA, PTH, calcium, cathecholamines and urinary metanephrine levels. Since there are 3 cases of MTC in patients between 3 and 6 years old, and diagnostic test data are not conclusive, we thoroughly recommend prophyilactic thyroidectomy at early ages, from 3 to 4 years old.
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PMID:[Prophylactic thyroidectomy in multiple endocrine neoplasia syndrome]. 2040 52

The object of this work was to compare the frequency of three polymorphic changes in the RET proto-oncogene: L769L, S836S, and S904S in patients with medullary thyroid carcinoma (MTC; n = 246) and in the general population (n = 420 for single-nucleotide polymorphism [SNP] L769L and S904S; n = 411 for SNP 836). We tried to investigate how the harbored SNPs affect the age at onset of sporadic medullary thyroid carcinoma (sMTC) and MTC in carriers of known pathogenic mutations at codons 634 and 791 of the RET gene. A statistically significant difference was found in the frequency of the heterozygous change L769L in patients with sMTC (48.3%) and in unaffected individuals (39.5%). The presence of the polymorphic change L769L in the RET gene predisposes to the development of sMTC and also lowers the age of onset of MTC in carriers of the homozygous polymorphic variant L769L. The presence of this polymorphic change in MTC patients carrying, at the same time, the RET codon 634 mutation lowers the age of onset of MTC in this group.
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PMID:The frequency of selected polymorphic variants of the RET gene in patients with medullary thyroid carcinoma and in the general population of central Poland. 2052 Nov 25

Increased expression of EGFR in metastases of human mammary carcinoma as compared to cells of the primary cancer suggests a contribution of EGFR to mammary carcinoma metastasis. To test for a positive correlation, we investigated 13762NF rat mammary adenocarcinoma cloned tumor cell lines of high (MTLn3) or low (MTC) metastatic potential. While MTC cells expressed barely detectable amounts of EGFR, MTLn3 cells expressed readily detectable levels of receptor. This was demonstrated in Northern blot analysis, in immunoprecipitation studies using metabolically labeled whole cell lysates and in Western blot analysis of membrane fractions. Cross-linking of radiolabeled ligand to intact cells identified on both cell types specific binding to a 170 kd protein, however, at much lower levels on low-metastatic MTC cells and not in sufficient amounts to estimate receptor numbers by Scatchard analysis. In contrast, Scatchard plot analysis of I-125-EGF binding to MTLn3 cells revealed the expression of about 10,000 high and 46,000 low affinity sites. Both cell lines expressed the ligand in comparable amounts as was demonstrated by using a specific rat TGFalpha cDNA probe in Northern blot and an antibody recognising membrane bound TGF in FACS analysis. Adhesion of MTC cells to immobilized collagen or fibronectin was rapid reaching 50% after 30 min while control MTLn3 cells demonstrated lower adhesion to collagen. Addition of 10 ng/ml EGF increased the rate and the maximal adhesion of MTLn3 cells to collagen G, while the adhesion kinetics of MTC cells to collagen G or fibronectin were unaffected.
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PMID:Expression of epidermal growth-factor receptor correlates with metastatic potential of 13762nf rat mammary adenocarcinoma cells. 2156 31


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