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, a receptor tyrosine kinase, has been evaluated as a candidate gene for multiple endocrine neoplasia type 2A and type 2B (MEN 2A and MEN 2B), for familial medullary thyroid carcinoma (FMTC), and for sporadic cases of medullary thyroid carcinoma (MTC) and pheochromocytomas. We determined the genomic structure of RET and used single-strand conformational polymorphism (SSCP) analysis to identify sequence variants in genomic DNA from families segregating MEN 2 and FMTC. In addition, we examined paired tumour and lymphocyte genomic DNAs from individuals with sporadic cases of MTC and pheochromocytoma. Altogether, we and others found 21 missense mutations in five cysteines clustered in the extra-cellular domain of RET (exons 10 and 11) associated with 111 MEN 2A and FMTC families. In contrast, a single point mutation that results in the substitution of threonine for methionine within the catalytic core of the tyrosine kinase domain (codon 918, exon 16) is responsible for all 66 reported cases of MEN 2B. Two missense mutations and a six base-pair deletion were identified in MTC tumour DNA, but no mutations were identified from pheochromocytoma tumour DNAs. A predictive DNA test for MEN 2A-associated mutations in RET has been developed that is based on detection of missense mutations by polymerase chain reaction (PCR) amplification and restriction endonuclease cleavage. A dominant oncogene model for the action of the RET gene product is proposed as a mechanism of action in MEN 2A, MEN 2B, FMTC and for at least some cases of sporadic MTC.
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PMID:The RET proto-oncogene and cancer. 759 67

One hundred and ninety-seven members of 28 kindreds with multiple endocrine neoplasia type 2A (MEN 2A) were screened for RET proto-oncogene exon 10 and 11 mutations. Seventy-one known affected individuals had mutations of codons 609, 618, 620 or 634, whereas 53 unaffected individuals had no abnormalities. Nineteen out of 54 individuals of unknown status, mostly children, had RET mutations. Four of these children had thyroidectomy based on this analysis and were found to have C-cell abnormalities. We identified one false negative mutation analysis because of a codon 691 polymorphism. We conclude that RET mutational analysis is a cost-effective and accurate method for determination of gene carrier status in MEN 2A.
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PMID:Clinical use of molecular information in the management of multiple endocrine neoplasia type 2A. 759 69

The International RET Mutation Consortium was first convened as part of the Fifth International Workshop on Multiple Endocrine Neoplasia, Stockholm, Sweden, in an attempt to analyse the relationship of RET mutation and disease phenotype in the autosomal dominantly inherited multiple endocrine neoplasia type 2 (MEN 2) syndromes. Out of 361 families studied, 41% had MEN 2A, 17.7% MEN 2B, 6.4% FMTC and the remaining subjects were unclassified. RET mutations were detected in 87.3% of families overall. Over 93% of MEN 2B families had the RET 918 ATG-->ACG mutation, while the most frequent mutation detected in MEN 2A families was cysteine codon 634 (87% of all mutations).
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PMID:Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. 759 70

Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome. MEN 2B is characterized by the combined occurrence of medullary thyroid carcinoma (MTC), pheochromocytoma, mucosal neuroma and Marfanoid habitus. Recently, a missense mutation in codon 918 of the proto-RET has been reported in the germ line of apparently distinct families with MEN 2B. In the present paper we first show a familial case of MEN 2B in Japan also to be associated with a germ line mutation in codon 918 of the proto-RET. The mutation was the substitution of a threonine for a methionine in the tyrosine kinase domain of the protein. The germ-like mutations of the proto-RET in MEN 2A and MEN 2B are the first examples of a dominantly acting oncogenic point mutation initiating human hereditary neoplasia.
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PMID:Germ line mutation in the RET proto-oncogene associated with familial multiple endocrine neoplasia type 2B: a case report. 759 47

To assess the pathophysiological role of the RET protooncogene in sporadic pheochromocytomas, we examined the 2 regions of the gene in which molecular defects are specifically associated with the multiple endocrine neoplasias (MEN) type 2A (the cysteine-rich domain encoded by exons 10 and 11), and type 2B (the tyrosine kinase domain encoded by exon 16). The sequences of both regions were amplified by reverse transcriptase-polymerase chain reaction (PCR) or PCR from tumor RNA and/or leukocyte DNA. The amplified fragments were analyzed by denaturing gradient gel electrophoresis using chemical clamps. In 28 patients with unilateral sporadic tumors, 6 RET mutations were found, 3 in the MEN 2A region, 3 in the MEN 2B region. Five patients had missense mutations: 2 in the MEN 2A region (C634W and D631Y), and 3 in the MEN 2B region (M918T). Analysis of leukocyte DNA in 3 of these patients confirmed that RET mutations were only present in tumor DNA. The sixth patient had lost exon 10 in the tumor complementary DNA as a result of the deletion of the dinucleotide -AG- at the 3'splice acceptor site of intron 9; this molecular defect was only found in the tumor DNA. Thus RET mutations of the MEN 2A and 2B regions are also found in about 20% of sporadic pheochromocytomas. We describe new types of molecular defects of the RET protooncogene in the MEN 2A region that involve noncysteine residues and loss of exon 10. Further studies should be extended to analyze the entire RET protooncogene. These findings have a profound clinical impact for the management of patients with supposedly sporadic pheochromocytomas.
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PMID:The RET protooncogene in sporadic pheochromocytomas: frequent MEN 2-like mutations and new molecular defects. 855 Jul 89

The expression of the receptor-like tyrosine kinase RET is associated with tumors, tissues or cell lines of neural crest origin. In addition RET products (Ret) are involved in determining cell fate during the differentiation of the enteric nervous system and during renal organogenesis. However, as yet, no direct evidence exists to indicate that the Ret kinase activity might interfere in a specific way with cellular differentiation, or proliferation, of a neural crest derived cell line. By using two constitutively activated forms of RET (RET/PTC1 and RET/PTC3) in transient transfection experiments, we have obtained evidence that active RET could reprogramme the gene expression pattern in the rat pheochromocytoma PC12 cell line. Transcription driven by gene promoters, such as NGFI-A and vgf, which belong, respectively, to primary and delayed response genes to nerve growth factor (NGF), and by the neuron-specific enolase (NSE) promoter, is rapidly induced by the expression of activated RET oncogenes. This induction is not elicited in other non neural derived cell types tested. We also demonstrate that endogenous ras activity is required for RET induction of these neural markers. Finally, in the RET/PTC transfected PC12 cells, NGF is unable to induce further their transcription. This suggests that RET/PTC could share an intracellular signalling pathway with the NGF-receptor.
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PMID:Activated RET/PTC oncogene elicits immediate early and delayed response genes in PC12 cells. 762 17

The RET proto-oncogene encodes a transmembrane receptor of the tyrosine kinase family, recently found to be the gene responsible for the multiple endocrine neoplasia type 2A and 2B syndromes. RET was found specifically activated, by gene rearrangement, in human thyroid carcinomas of the papillary subtype. In most cases the activation consisted of an in frame fusion of the RET tyrosine-kinase domain, at the carboxy-terminus, with heterologous genes at the amino-terminus. These chimeric oncogenes are collectively named RET/PTC. Two forms of these gene products, RET/PTC1 and RET/PTC3, have been tested for their ability to induce meiotic maturation in Xenopus oocytes. Injection of RET/PTC mRNAs into immature oocytes induced maturation-promoting-factor (MPF) activation and germinal vesicle breakdown (GVBD). The injected oocytes expressed polypeptides recognized by an anti-RET gene product antibody as well as by an antiphosphotyrosine antibody, indicating activation of the tyrosine-kinase domain. The RET/PTC induced maturation was dependent on endogenous ras; in fact, the coinjection of RET/PTC mRNA with a neutralizing anti-ras antibody blocked oocytes maturation without interfering with the accumulation and tyrosine-phosphorylation of the RET/PTC protein.
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PMID:Activated RET oncogene products induce maturation of xenopus oocytes. 762 18

The RET proto-oncogene is expressed in human medullary thyroid carcinoma and pheochromocytoma. Recently germline mutations of the RET proto-oncogene were reported in four syndromes (MEN 2A, MEN 2B, familial medullary thyroid carcinoma and Hirschprung's disease) and somatic mutation was also found in sporadic medullary thyroid carcinoma. To determine the incidence of RET mutations in medullary thyroid carcinoma in Japan, we investigated 14 medullary thyroid carcinomas (comprising 1 case of MEN 2A, 1 case of MEN 2B, 2 cases of familial medullary thyroid carcinoma and 10 cases of sporadic). Tumors from all cases were screened by PCR-SSCP on exons 10 and 11. DNA sequencing on these exons was performed for the hereditary medullary thyroid carcinoma cases. The PCR products of exon 16 from tumor DNA were analyzed by means of Fok1 restriction enzyme digestion analysis and mutations confirmed by DNA sequencing. We found no structural abnormalities in either exon 10 or exon 11 in any of the cases examined, but in four of 10 sporadic cases we detected a common point mutation at codon 918 (ATG to ACG) in exon 16, where methionine was replaced with threonine. Our results support the theory that a point mutation of exon 16 of the RET proto-oncogene may be related to the oncogenesis of sporadic medullary thyroid carcinomas. However, further studies on the entire RET proto-oncogene are needed to clarify the relationship between its expression and thyroid tumorigenesis.
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PMID:A single missense mutation in codon 918 of the RET proto-oncogene in sporadic medullary thyroid carcinomas. 762 69

Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most common cause of congenital bowel obstruction with an incidence of 1 in 5000 live births. Recently, linkage of an incompletely penetrant, dominant form of HSCR was reported, followed by identification of mutations in the RET receptor tyrosine kinase. To determine the frequency of RET mutations in HSCR and correlate genotype with phenotype, we have screened for mutations among 80 HSCR probands representing a wide range of phenotypes and family structures. Polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) analysis of RET's 20 exons for mutations among probands revealed eight putative mutations (10%). Sequence changes, which included missense, frameshift and complex mutations, were detected in both familial and isolated cases, among patients with both long- and short-segment HSCR and in three kindreds with other phenotypes (maternal deafness, talipes and malrotation of the gut, respectively). Two mutations (C609Y and C620R) we identified have previously been associated with multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma (MTC) and, on rare occasions, HSCR. Thus, while HSCR family members may be at risk for developing neuroendocrine tumors, it follows that identical mutations in RET may be able to participate in the pathogenesis of distinct phenotypes. Our data suggest that: (i) the overall frequency of RET mutations in HSCR patients is low and therefore, other genetic and/or environmental determinants contribute to the majority of HSCR susceptibility, and (ii) at present, there is no obvious relationship between RET genotype and HSCR phenotype.
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PMID:Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. 763 41

The RET and the Pax 3 genes have recently been shown to account for autosomal dominant Hirschsprung's disease (HSCR) and Waardenburg syndrome type 1 (WS1) respectively, which led us to consider them as candidate genes in the WS/HSCR association. Linkage analyses performed in a consanguineous WS/HSCR family support the view that neither the RET locus nor the Pax 3 locus are involved in the disease phenotype. Hence, at least one further locus altering neural crest cell development is responsible for the pleiotropic features observed in the WS/HSCR association.
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PMID:Exclusion of RET and Pax 3 loci in Waardenburg-Hirschsprung disease. 764 65


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