Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid carcinoma (FMTC) are autosomal dominant inherited cancer syndromes with incomplete penetrance. Following the identification of mutations in the RET proto-oncogene that segregate with the disease phenotype in MEN2A, MEN2B, and FMTC, genetic screening of individuals with mutations in RET may be performed. We have employed restriction endonuclease digestion of polymerase chain reaction products as an alternative to sequence analysis for rapid identification of mutant gene carriers in families in which MEN2A and FMTC are segregating. Twenty-one Australasian MEN2A and FMTC families have been screened for mutations in a cysteine-rich region of the RET proto-oncogene. Seven independent mutations were identified in key individuals in 16 of these families. We have identified a mutation in codon 620, 2053 T-->C (Cys620Arg), and two mutations in codon 634 of exon 11 of RET, 2095 T-->C (Cys634Arg) and 2096 G-->A (Cys634Tyr), all three of which were present in both MEN2A and FMTC families.
 ...
PMID:A rapid screening method for the detection of mutations in the RET proto-oncogene in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma families. 783 99

How do distinct protein-tyrosine kinases activate specific down-stream events? Src-homology-2 (SH2) domains on tyrosine kinases or targets of tyrosine kinases recognize phosphotyrosine in a specific sequence context and thereby provide some specificity. The role of the catalytic site of tyrosine kinases in determining target specificity has not been fully investigated. Here we use a degenerate peptide library to show that each of nine tyrosine kinases investigated has a unique optimal peptide substrate. We find that the cytosolic tyrosine kinases preferentially phosphorylate peptides recognized by their own SH2 domains or closely related SH2 domains (group I; ref. 3), whereas receptor tyrosine kinases preferentially phosphorylate peptides recognized by subsets of group III SH2 domains. The importance of these findings for human disease is underscored by our observation that a point mutation in the RET receptor-type tyrosine kinase, which causes multiple endocrine neoplasia type 2B, results in a shift in peptide substrate specificity.
 ...
PMID:Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. 784 56

Germline mutations within one of six codons of the RET proto-oncogene account for the majority of cases of multiple endocrine neoplasia (MEN) type 2A and type 2B and familial medullary thyroid carcinoma (FMTC). MEN 2A and FMTC mutations characterised thus far occur exclusively in the cysteine-rich domain of the extracellular region of RET. We now report a missense mutation in the intracellular tyrosine kinase domain of RET in the germline of a family with FMTC that does not have a cysteine codon mutation. In this family, the mutation, which alters GAG (Glu) to GAC (Asp) at codon 768, segregates with the FMTC phenotype. The same mutation was also detected in sporadic MTC but not in corresponding constitutional DNA, confirming that it is likely to be of pathological significance rather than a rare polymorphism.
 ...
PMID:A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. 784 75

Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome which affects thyroid C cells, and with variable frequency, the adrenal medulla, parathyroid and enteric autonomic ganglia. The syndrome is due to germline mutation in the receptor tyrosine kinase gene, RET. We have recently shown an unexpected correlation between one particular RET mutation, cys634-->arg, and the probability of parathyroid involvement in families with MEN 2A. Here we use haplotype analysis in the families to show that this correlation is not explained by a single founder chromosome which carries both the cys634-->arg mutation and a separate allele conferring susceptibility to parathyroid abnormality, but is probably due to the cys634-->arg mutation itself. The results also indicate that new mutations to MEN 2 are not infrequent.
 ...
PMID:Haplotype analysis of MEN 2 mutations. 784

Mutations in the RET protooncogene have recently been demonstrated in families with multiple endocrine neoplasia (MEN) types 2A and 2B. We have studied pheochromocytomas from 29 individuals who had no clinical evidence of MEN-2A or -2B to determine the frequency of germline and/or somatic mutations in exons 10, 11, and 16 of the RET protooncogene. Of the 29 tumors examined, 3 (10%) were found to have a mutation in 1 of the 3 exons. These mutations were not found in the DNA from the peripheral blood from these individuals, indicating that the mutations in the tumors were somatic in origin. Although we cannot exclude the possibility of mutations in other regions of the RET protooncogene, our data suggest that 1) individuals presenting with apparently sporadic pheochromocytomas are not likely to have undiagnosed MEN-2A or -2B; and 2) somatic mutations in exons 10, 11, and 16 in the RET protooncogene contribute to the process of tumorigenesis in a small percentage of sporadic pheochromocytomas.
 ...
PMID:Mutations in the RET protooncogene in sporadic pheochromocytomas. 785 30

Multiple endocrine neoplasia type 2A (MEN2A) is a dominantly inherited cancer syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. The gene responsible for MEN2A was localized by linkage analysis to chromosome 10q11.2 in 1987, and recently mutations in RET, a proto-oncogene in the candidate region, were discovered in patients with MEN. The majority of mutations found so far in MEN2A patients have been located in nucleotide sequences encoding cysteine residues in the extracellular domain of RET. To characterize MEN2A germline alterations in the Japanese population, we screened DNA from eight unrelated patients for mutations in exons 10 and 11 of the RET proto-oncogene and found mutations in all eight patients, at codons 618, 620, or 634; each of these sites encodes a cysteine residue in the extracellular domain of RET. The mutations were confirmed in other affected individuals in the respective families by digestion of polymerase chain reaction (PCR) products containing the mutated codons with restriction enzymes (Rs alpha I, CfoI, or AluI) for which cleavage sites had been generated by the specific genetic alteration. These PCR-restriction enzyme systems will be useful for genetic diagnosis in members of families carrying these mutations.
 ...
PMID:Germline mutations of the RET proto-oncogene in eight Japanese patients with multiple endocrine neoplasia type 2A (MEN2A). 786 65

The c-ret proto-oncogene encodes a receptor tyrosine kinase that plays important roles in human disease and in normal mammalian development. Mutations in the human RET gene are associated with multiple endocrine neoplasia syndromes and Hirschsprung's disease in humans, while targeted mutagenesis of murine c-ret resulted in severe developmental abnormalities affecting the excretory and peripheral nervous systems. To examine the evolutionary conservation of the ret protein sequence and its developmental expression pattern, we isolated and sequenced cDNA clones of chicken c-ret and examined its expression in chick embryos and adult tissues. The cytoplasmic domains of chicken and human ret were relatively well conserved (91% similar), but the extracellular domains were more divergent (68% similar), although the conservation of cysteine residues in this region suggests a conserved secondary structure. As in mouse and human, chicken c-ret encodes two protein isoforms. The number and sizes of the transcripts were similar to those in human and mouse cells, and during chick embryogenesis, c-ret mRNA was observed in many of the same sites as in the mouse, including the Wolffian duct and ureteric bud, the enteric, dorsal root, sympathetic and facioacoustic ganglia, and the ventral spinal cord. Evolutionary differences in expression were observed in the trigeminal ganglion, the ventral roots of the spinal cord, the mesenchymal cells of the branchial arches and the adult testes. The results are discussed with regard to the role of the ret receptor in normal development and disease.
 ...
PMID:Isolation and characterization of a chicken homolog of the c-ret proto-oncogene. 786 41

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.
 ...
PMID:Point mutation of the RET proto-oncogene in the TT human medullary thyroid carcinoma cell line. 786 88

RET proto-oncogene products are involved in neural crest development, and constitutional RET mutations are associated with syndromes characterized by tumors of neural crest origin. To study the regulation of RET transcription during neuronal differentiation we analyzed RET expression in neuroblastoma cell lines treated with various differentiating agents. A marked increase in RET mRNA levels was observed in all the cell lines examined shortly after retinoic acid (RA) treatment and before the onset of detectable morphological changes. Upregulation of RET expression was also found in SK-N-BE cells induced to differentiate by 12-O-tetradecanoylphorbol-13-acetate, glial cell-conditioned medium, alpha or gamma interferon, and in SH-SY-5Y cells exposed to nerve growth factor. Induction of RET expression by RA occurred in the absence of de novo protein synthesis. On the other hand, cycloheximide treatment by itself caused upregulation of RET transcripts. These results indicate that the positive transcriptional regulation of RET is closely associated with early neuronal differentiation and suggest that a negative regulatory factor/s controls RET transcription in neuroblastoma cells. Finally, anti-Ret antibodies immunoprecipitated four bands with apparent molecular weights of 150, 155, 170, and 175 kDa in RA-induced SK-N-BE cells. These bands likely represent differently glycosylated forms of the two RET primary products (117 and 122 kDa) detected in tunicamycin-treated cells.
 ...
PMID:Induction of RET proto-oncogene expression in neuroblastoma cells precedes neuronal differentiation and is not mediated by protein synthesis. 786 26

It has been shown that in contrast to peripheral fat, visceral fat is an important risk factor for cardiovascular diseases and diabetes. In this study, we investigated whether dexfenfluramine (dF), a compound known to decrease body fat, affects fat mass differentially in various regions of the body. We used a moderately obese rat model fed a high-fat diet (40% fat). After 35 days on the diet, rats were divided into three groups: a dF-treated group ([D]2.5 mg/kg intraperitoneally twice daily), a pair-fed group (Cp), and a control group (C) fed ad libitum. C and Cp rats were injected with saline. After 4 weeks of treatment, body fat, fat cell morphology, and metabolism were determined in subcutaneous (inguinal [ING]) and visceral (retroperitoneal [RET] and mesenteric [MES]) fat tissues. Food intake in D and Cp rats was similar, and was lower than in the C group. In comparison to Cp and C rats, D rats had lower body weight and body fat, smaller ING and RET fat pad weights, and smaller fat cell size in all depots. No significant differences were observed in fat mobilization between groups; however, fat accumulation tended to be lower in D rats. These data suggest that dF has an effect on adipose tissue independent of its effect on food intake. However, this effect seems to occur without regional specificity.
 ...
PMID:Effect of dexfenfluramine on fat mass distribution in a high-fat rat model. 786 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>