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)

The RET proto-oncogene encodes a tyrosine-kinase receptor specifically expressed in tissues of neuroectodermal origin. Recently specific point mutations of RET have been demonstrated to be responsible for the Multiple Endocrine Neoplasia type 2A and 2B and Familial Medullary Thyroid Carcinoma syndromes, characterized by the occurrence of medullary thyroid carcinomas. Here we report that a human medullary thyroid carcinoma cell line, the TT cell line, harbours a MEN2A-type mutation, specifically a cysteine to triptophan substitution at the level of the RET codon 634. This mutation is heterozygous and both normal and mutated alleles are expressed. We suggest that the TT cell line could be a useful cell system to investigate the role played by the RET oncogene in the transformation and differentiation of human thyroid C-cells.
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PMID:Point mutation of the RET proto-oncogene in the TT human medullary thyroid carcinoma cell line. 786 88

Somatic RET mutations have been identified in a variable proportion (about 30-70%) of sporadic Medullary Thyroid Carcinoma (MTC) cases. They are represented by the Met918Thr substitution (exon 16) typical of Multiple Endocrine Neoplasia type 2B (MEN2B) and, to a lesser extent, by nucleotide changes occurring at one of five critical cysteine residues (exons 10 and 11) typical of MEN type 2A (MEN2A). An in vitro transforming activity has already been demonstrated for these mutations. A few different MTC somatic mutations have been reported so far whose biological activity has still to be tested. In this paper we report the identification, in two MTC tumor samples, of two interstitial deletions of 48 bp and 6 bp occurred in exons 10 and 11 respectively. Both were somatic heterozygous in frame mutations, not involving any cysteine residue. Moreover, the expression of a full length RET cDNA carrying one of the two deletions demonstrated a strong transforming capacity in NIH3T3 cells.
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PMID:Somatic in frame deletions not involving juxtamembranous cysteine residues strongly activate the RET proto-oncogene. 919 Oct 60

The susceptibility gene for hereditary Medullary Thyroid Carcinoma (MTC) is the RET proto-oncogene. The aim of this study was to evaluate the prevalence of common germline RET mutations in exons 10 and 11 among Iranian MTC patients. Fifty-seven non-related MTC patients were examined in this study (Females: Males =1.2:1.0, Mean age = 40.0 +/- 11.5 years) and the existence of mutations was assessed through the PCR-RFLP technique. The only Multiple Endocrine Neoplasia type 2A (MEN2A) patient displayed a C634W mutation in exon 11. Among 53 apparently sporadic MTC patients, one patient showed a C620R mutation in exon 10 and two other patients displayed C624Y mutations in exon 11 of RET proto-oncogene. Neither the only Multiple Endocrine Neoplasia type 2B (MEN2B) patient nor two Familial MTC patients was found to carry germline mutations in exons 10 and 11. This study reports, for the first time, the prevalence of common RET mutations among Iranian, apparently sporadic MTC patients, underlining the critical importance of screening for RET mutations in such patients.
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PMID:Germline RET mutations in exons 10 and 11: an Iranian survey of 57 medullary thyroid carcinoma cases. 1762 57

The currently available genetic tests for identification of the RET proto-oncogene mutation offer the possibility of prospective successful therapy before the hyperplasia of C-cells evolve to Medullary Thyroid Carcinoma. We present our experience regarding the preventive thyroidectomy of family members with history of Medullary Thyroid Carcinoma, who were found to be heterozygote for mutant RET proto-oncogene. We have retrospectively reviewed 19 members of 6 families with history of Medullary Thyroid Carcinoma, who were heterozygote for mutant RET protooncogene and underwent prophylactic thyroidectomy. All patients included in this series were below twenty years of age. The Medullary Thyroid Carcinoma was asymptomatic and the mutation of RET protooncogene has been also documented pre-operatively in all of them. All patients had undergone total thyroidectomy, while 1 with pheochromocytoma had undergone also left epinephridectomy. Fourteen patients (73.68%) had undergone lymph-nodes resection (in 10 of them the resection was central, in 3 unilateral and in 1 bilateral). Although none of our patients suffered from hyperparathyroidism, 7 parathyroid glands have been also resected from 3 patients, while auto-transfusion has been performed in one. In all patients, preoperative measurement of the calcitonin blood levels before and after stimulation with pentagastrin has been performed.
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PMID:Preventive thyroidectomy in patients with hereditary medullary thyroid carcinoma found heterozygote for mutant RET proto-oncogene. 2115 Aug 41

About 30% of hereditary Medullary Thyroid Carcinoma (MTC) have been demonstrated to harbour imbalance between mutant and wild-type RET alleles. We studied the RET copy number alterations (RET CNA) in 65 MTC and their correlation with RET mutation and patients' outcome. Fluorescence in situ Hybridization and Real-time PCR revealed RET CNA in 27.7% MTC but only in a variable percentage of cells. In sporadic MTC, RET CNA were represented by chromosome 10 aneuploidy while in hereditary MTC by RET amplification. A significant higher prevalence of RET CNA was observed in RET mutated MTC (P=0.003). RET CNA was also associated to a poorer outcome (P=0.005). However, the multivariate analysis revealed that only RET mutation and advanced clinical stage correlated with the worst outcome. In conclusion, 30% MTC harbour RET CNA in variable percentage of cells suggesting cell heterogeneity. RET CNA can be considered a poor prognostic factor potentiating the poor prognostic role of RET mutation.
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PMID:Chromosome 10 and RET gene copy number alterations in hereditary and sporadic Medullary Thyroid Carcinoma. 2186 42

This case report emphasizes the fact that all patients with Hirschsprung disease should be screened for RET Oncogene mutation as there is a well known association between Hirschsprung Disease and Multiple Endocrine Neoplasia (MEN) Type 2A. It also reminds us that Medullary Thyroid Carcinoma is known to cause elevated levels of CEA which does not originate from gastrointestinal tract.
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PMID:Hirschsprung disease of the colon, a vaginal mass and medullary thyroid cancer - a RET oncogene driven problem. 2281 60

Endocrine tumors of thyroid, adrenal and parathyroid glands may be due to germline and inheritable mutations in 5-30% of patients. Medullary Thyroid Carcinoma, Pheochromocytoma, Paraganglioma, and Familial Primary Hyperparathyroidism are the most frequent entity. Hereditary endocrine tumors usually have a suggestive familial history; they occur earlier than sporadic variants, are multifocal, and have increased recurrence rates. They may be present as isolated variant or associated to other neoplasms in a syndromic setting. Genetic diagnosis should be preferably available before surgery because specific and targeted operative management are needed to achieve the best chance of cure. This review was aimed to discuss the surgical approaches for some of the most frequent hereditary endocrine tumors of thyroid, adrenal and parathyroid glands, focusing on medullary thyroid carcinoma, Pheochromocytoma, Paraganglioma and hereditary primary hyperparathyroidism (pHPT). Hereditary Medullary Thyroid Carcinoma is caused by RET mutations, and may be associated to Pheochromocytomas in MEN 2 setting. Total thyroidectomy and at least central neck nodal dissection is required. The availability of genetic screening allows prophylactic or early surgery in asymptomatic patients, with subsequent definitive cure. Hereditary Pheochromocytomas may be present in several syndromes (MEN 2, VHL, NF1, Paraganglioma/Pheochromocytoma syndrome); it may involve both adrenals; in these cases, a cortical sparing adrenalectomy should be performed to avoid permanent hypocorticosurrenalism. Hereditary Primary Hyperparathyroidism may frequently occur associated to MEN 1, MEN 2A, MEN 4, Hyperparathyroidism-Jaw Tumor Syndrome; it may involve all the parathyroid glands, requiring subtotal parathyroidectomy or total parathyroidectomy plus autotransplantation. In some cases, a selective parathyroidectomy might be performed.
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PMID:Surgical approaches in hereditary endocrine tumors. 2845 35

It is now known that "gain of function" mutations of RET (REarranged during Transfection) kinase are specific and key oncogenic events in the onset of thyroid gland cancers such as the Medullary Thyroid Carcinoma (MTC). Although a number of RET inhibitors exist and are capable of inhibiting RET variants, in which mutations are outside the enzyme active site, the majority becomes dramatically ineffective when mutations are within the protein active site (V804L and V804M). Pursuing a receptor-based virtual screening against the kinase domain of RET, we found that compound 5 is able to inhibit efficiently both wild type and V804L mutant RET. Compound 5 was able to significantly reduce proliferation of both commercially available TT cell lines and surgical thyroid tissues obtained from patients with MTC and displayed a suitable drug-like profile, thus standing out as a promising candidate for further development towards the treatment of clinically unresponsive MTC.
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PMID:Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors. 2954 36

Sporadic Medullary Thyroid Carcinoma (sMTC) is a rare but aggressive thyroid tumor. RET and RAS genes are present in about 50%-80% of cases, but most of the remaining cases are still orphan of a genetic driver. We studied the largest series of sMTC by deep sequencing to define the mutational landscape. With this methodology we greatly reduced the number of RET- or RAS-negative cases and we confirmed the central role of RET and RAS mutations. Moreover, we highlighted the bad prognostic role of RET mutations in sMTC and consolidated the favorable prognostic role of RAS mutations. For the first time, we showed that the variant allele frequency represents an additional prognostic marker inside the group of RET-mutated sMTC.
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PMID:Genetic Landscape of Somatic Mutations in a Large Cohort of Sporadic Medullary Thyroid Carcinomas Studied by Next-Generation Targeted Sequencing. 3160 46

Medullary Thyroid Carcinoma (MTC) is a rare neuroendocrine cancer that accounts for 1-2% of thyroid cancers in the United States (U.S.). While most cases are sporadic, 25% of MTC cases are hereditary. These hereditary cases occur in the setting of Multiple Endocrine Neoplasia Type 2A (MEN2A) or 2B (MEN2B) driven by mutations in the Rearranged during Transfection RET proto-oncogene. This article discusses hereditary MTC in the setting of MEN2 and the treatment options available for it. The first line treatment for this disease is typically a total thyroidectomy and tyrosine kinase inhibitors. Two tyrosine kinase inhibitors, vandetanib and cabozantinib, have been approved for treatment of advanced MTC, but options beyond those are limited. However, several promising treatments are being studied, which are discussed in this review.
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PMID:Update on the Treatment of Medullary Thyroid Carcinoma in Patients with Multiple Endocrine Neoplasia Type 2. 3229 10


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