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 codes for a receptor-type tyrosine-kinase with to date unknown ligand. Recently, germline point-mutations in RET cysteine codons of the extracellular cysteine-rich domain (encoded by exons 10 and 11) and in the tyrosine-kinase domain (encoded by exon 16) at codon 918, have been associated with the syndromes of multiple endocrine neoplasia (MEN) type 2A, MEN type 2B and familial medullary thyroid carcinoma (FMTC). In our recent studies we have analyzed tumor and germline DNA extracted from formalin-fixed and paraffin-embedded specimens of 45 patients and additional blood samples of 38 possible MEN 2 gene carriers for the presence of RET point mutations in exons 10 and 11 by non-radioactive single strand conformation polymorphism analysis (PCR-SSCP) and for exon 16 by heteroduplex gel electrophoresis. Mutational analysis was performed by fluorescence-based dideoxy terminator cycle sequencing of PCR-products with an automated DNA sequencer. Materials included 19 patients with MEN 2A associated tumors (13 medullary thyroid carcinomas, 6 pheochromocytomas), 3 patients with MEN 2B associated medullary thyroid carcinomas and 23 patients with clinically sporadic tumors (16 medullary thyroid carcinomas, 7 phenochromocytomas). In all 19 MEN 2A patients we found RET germline point-mutations either at cysteine codons 634 (14), 630 (1) in exon 11 or at codon 618 (4) in exon 10. All 3 MEN 2B patients demonstrated germline point mutations at codon 918 (Met-->Thr) in exon 16. In 2 patients with clinically sporadic medullary thyroid carcinomas we found a point mutation at codon 634 both in DNA of the tumor and normal tissue, indicating the presence of a de novo germline mutation. In 5 sporadic medullary thyroid carcinomas and 2 pheochromocytomas we found a somatic point mutations were identified in 11 patients. Our results indicate that mutational analysis of the RET proto-oncogene is not only suitable to identify and subtype MEN 2 gene carriers using blood DNA but also to distinguish sporadic from inherited medullary thyroid carcinomas and phenochromocytomas analyzing DNA extracted from archival tissue specimens.
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PMID:Rudolf-Virchow-Preis 1995. The role of RET proto-oncogene mutation analysis in the diagnosis of multiple endocrine neoplasia type 2 (MEN 2) gene carriers and in the discrimination of sporadic and familial medullary thyroid carcinomas and pheochromocytomas. 860 Jun 71

Mutations in the RET proto-oncogene are associated with the pathogenesis of medullary thyroid carcinoma (MTC). In an attempt to understand this process, we examined microdissected subpopulations from MTC and multiple metastases from these tumors. Approximately 80% of sporadic MTC's had at least one subpopulation with the RET codon 918 mutation, which is a mutation previously detected in sporadic MTC as a somatic mutation and in multiple endocrine neoplasia type 2B as a germline mutation. However, the distribution of this mutation was nonhomogeneous, occurring only in subpopulations in most tumors and among subsets of multiple metastases, thus implying that although the codon 918 mutation could be an early event, it is not necessarily an early or essential event in tumorigenesis. This heterogeneity suggests either that the codon 918 mutation can arise as an event in progression within a metastatic clone or within a single tumor, or that MTC can be of polyclonal origin. Of significance, one of two multiple endocrine neoplasia type 2A MTCs carried a somatic mutation at codon 918, in addition to the RET mutation present in the germline. We found no correlation between the presence of other somatic genetic events, such as loss of heterozygosity on chromosome arms 1p and 22q, and RET mutation status in the various subpopulations of MTC.
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PMID:Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. 861 67

The RET proto-oncogene encodes a member of the receptor tyrosine kinase family. Multiple endocrine neoplasia type 2B (MEN 2B) is caused by the mutation of a conserved methionine to a threonine in the catalytic domain of the RET kinase. When the MEN 2B point mutation was introduced into the epidermal growth factor (EGF) receptor (M857T EGFR), the intrinsic tyrosine kinase activity of the mutant receptor was similar to that of wild-type EGF receptor and remained ligand-dependent. However, the mutant receptor showed an enhanced transforming capacity compared to the wild-type receptor as judged by its ability to mediate the growth of NIH 3T3 cells in soft agar. Using the oriented peptide library approach to examine substrate specificity, the M857T mutation was found to be associated with a decrease in the selectivity of the receptor for Phe and an increase in the selectivity for acidic residues at the P + 1 position as compared to wild-type EGF receptor. Short-term responses to EGF were similar in cells expressing wild-type and M857T EGF receptors. However, significant differences in receptor down-regulation were observed between the two receptors. These data demonstrate that the MEN 2B point mutation alters the substrate specificity of receptor tyrosine kinases and suggest that the enhanced oncogenesis associated with the MEN 2B mutation may be due in part to alterations in receptor regulation.
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PMID:The multiple endocrine neoplasia type 2B point mutation alters long-term regulation and enhances the transforming capacity of the epidermal growth factor receptor. 862 56

Gene rearrangements activating the RET proto-oncogene are frequently associated with human thyroid carcinomas belonging to the papillary subtype. These arrangements cause the fusion of the tyrosine-kinase domain of RET to the 5'-terminal region of different genes creating the RET/PTC chimeric oncogenes. Here we report the generation of transgenic mice lines expressing the RET/PTC1 oncogene under the control of the thyroid-specific rat thyroglobulin promoter. RET/PTC1-transgenic mice developed thyroid tumors displaying the histological aspect of papillary carcinomas. These tumors were slowly progressive and did not cause premature death of the animals. Two additional mice developed areas of thyroid hyperplasia. Immunohistochemical and reverse-transcriptase polymerase chain reaction analyses confirmed the thyroid-specific expression of the transgene. Given the frequency of activating rearrangements of RET in human papillary thyroid carcinomas we conclude that this animal system could be a good model for studying the neoplastic progression of thyroid carcinomas.
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PMID:Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. 862 3

Inherited cancer syndromes predispose an individual to development of specific tumors. Somatic and germline mutations in the same tumor suppressor gene, as described in Knudson's two-mutation model, are well recognized. Inherited mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, predispose individuals to the multiple endocrine neoplasia type 2 (MEN 2) cancer syndromes. The major component tumor of these syndromes is medullary thyroid carcinoma (MTC). To date, somatic mutations in RET have not been identified in tumors from individuals with MEN 2, although they have been well documented in sporadic MEN 2-related tumors. We have identified, among 16 MEN 2 cases with well-defined RET germline mutations, a somatic missense mutation at codon 918 of RET in 3 of 15 MTCs and in a sample with hyperplastic C-cells (presumed precursor to hereditary MTC). We suggest that the presence of a somatic mutation, in addition to the preexisting germline mutation in hereditary MTCs, may contribute to tumorigenesis in vivo.
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PMID:Germline and somatic mutations in an oncogene: RET mutations in inherited medullary thyroid carcinoma. 864 Aug 6

We demonstrate that a Hirschsprung (HSCR) mutation in the tyrosine kinase domain of the RET proto-oncogene abolishes in cis the tyrosine-phosphorylation associated with the activating mutation in multiple endocrine neoplasia type 2A (MEN2A) in transiently transfected Cos cells. Yet the double mutant RET2AHS retains the ability to form stable dimers, thus dissociating the dimerization from the phosphorylation potential. Co-transfection experiments with single and double mutants carrying plasmids RET2A and RET2AHS in different ratios drastically reduced the phosphorylation levels of the RET2A protein, suggesting a dominant-negative effect of the HSCR mutation. Also, the phosphorylation associated with the multiple endocrine neoplasia type 2B (MEN2B) allele was affected in experiments with single and double mutants carrying plasmids co-transfected under the same conditions. Finally, analysis of the enzymic activity of MEN2A and MEN2B tumours confirmed the relative levels of tyrosine phosphorylation observed in Cos cells, indicating that this condition, in vivo, may account for the RET transforming potential.
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PMID:A mutation in the RET proto-oncogene in Hirschsprung's disease affects the tyrosine kinase activity associated with multiple endocrine neoplasia type 2A and 2B. 867 46

Parathyroid tumors occur either sporadically or as part of inherited syndromes such as multiple endocrine neoplasia (MEN) types 2A and 2B. The development of both of these familial syndromes has been related to specific germline gain-of-function mutations predominantly in exons 10 and 11 (MEN 2A) and 16 (MEN 2B) of the RET proto-oncogene. The same mutations have also been implicated in the pathogenesis of sporadic medullary thyroid carcinoma and sporadic pheochromocytoma. The RET mutations are thought to have a transforming effect only in cells of neural crest origin such as thyroid parafollicular (C-cells) and adrenal chromaffin cells, which normally express the RET proto-oncogene. Expression of RET messenger RNA has not yet been studied in the parathyroid, however, we demonstrate in this study by a sensitive, semiquantitative RT-PCR technique and in situ hybridization, that RET is expressed in MEN 2A parathyroid tumors and in sporadic adenomas. Although DNA from a parathyroid tumor of a MEN 2A patient displayed an expected mutation, none of the previously described MEN 2A or 2B mutations were found in DNA of 34 sporadic adenomas. Our data suggest that parathyroid disease is an integral part of the MEN 2A syndrome, but that MEN 2 mutations in RET rarely play a part in the pathogenesis of sporadic parathyroid tumors.
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PMID:Role of the RET proto-oncogene in sporadic hyperparathyroidism and in hyperparathyroidism of multiple endocrine neoplasia type 2. 867

Primary cutaneous amyloidosis is a relatively common skin disease in Southeast Asia, South America, and the Republic of China. Although most cases are sporadic, some patients have a family history, suggesting that genetic factors may play a role in its pathogenesis. Some patients with multiple endocrine neoplasia type 2A also have a clinical picture of primary cutaneous amyloidosis. It is thus suggested that the gene of familial primary cutaneous amyloidosis is linked to the pericentromeric region of chromosome 10, the location of the RET proto-oncogene. We have carried out linkage analysis in seven families with cutaneous amyloidosis using four dinucleotide repeat markers from the RET region. Negative lod scores at all recombination frequencies were obtained. We thus conclude that there is no evidence for linkage between Chinese families with primary cutaneous amyloidosis and the pericentromeric region of chromosome 10. The distinct genetic basis, plus their apparent phenotypic differences in sex ratio, age of onset, and sites of cutaneous lesions, suggests that familial primary cutaneous amyloidosis includes clinical subtypes attributable to genetic heterogeneity.
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PMID:Genetic heterogeneity of familial primary cutaneous amyloidosis: lack of evidence for linkage with the chromosome 10 pericentromeric region in Chinese families. 875 35

Mutations in the RET proto-oncogene have been found in a large proportion of families affected by the multiple endocrine neoplasia type 2 syndrome and in familial and sporadic Hirschsprung disease. This review discusses the role of the RET receptor tyrosine kinase in the etiology of these dominantly inherited disorders of neural crest development. In addition, the role of genetic screening is considered in the identification and clinical management of individuals at risk for these diseases.
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PMID:RET mutations in multiple endocrine neoplasia type 2 and Hirschsprung disease. 877 23

To assess the feasibility of screening for multiple endocrine neoplasia type 2A (MEN 2A), the authors used DNA sequence analysis to evaluate the RET proto-oncogene in a kindred with MEN 2A. The kindred consisted of 95 members (1 to 79 years of age) and their spouses, and spanned five generations. Genomic DNA was extracted from peripheral blood lymphocytes or lymphoblastoid cell lines established from the family members, and the RET gene was amplified by polymerase chain reaction (PCR) using RET-specific primers (10q 11.2) and was sequenced. Periodic endocrine screening also was performed, by measuring the plasma calcitonin concentration after provocation with pentagastrin (0.5 microgram/kg intravenously) to assess its reliability for detecting the associated neoplasms. Nineteen patients were confirmed to have MEN 2A by medical records or the screening program. The DNA sequence of the PCR products from clinically established MEN 2A patients showed a mutation at codon 634 (TGC-->CGC) that resulted in an amino acid change from cysteine to arginine. Endocrine screening tests showed that six other family members had a mutated RET protooncogene. DNA sequencing can detect high-risk cases at a preclinical stage of the disease. The establishment of mutated MEN 2A gene carriers allows pediatric surgeons to consider total thyroidectomy at a very early stage of neoplasm development (C-cell hyperplasia) or even prophylactically.
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PMID:Germline mutations of the RET proto-oncogene in pedigree with MEN type 2A: DNA analysis and its implications for pediatric surgery. 878 1


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