Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The susceptibility loci for the three multiple endocrine neoplasia (MEN) type 2 syndromes have been mapped to the region of chromosome 10q11.2 containing the RET proto-oncogene, which codes for a receptor tyrosine kinase. The majority of MEN 2A and familial medullary thyroid carcinoma results from missense mutations within one of five cysteine codons in the extracellular domain of the RET proto-oncogene. We now report a missense mutation, resulting in the substitution of a threonine for a methionine at codon 918 in the tyrosine kinase catalytic domain, in the germline of 26 of 28 apparently distinct families with MEN 2B. DNA from five of 13 apparently sporadic MTC and one of 12 apparently sporadic phaeochromocytomas harboured a similar mutation, but the corresponding germline DNA was wildtype in each case.
Hum Mol Genet 1994 Feb
PMID:Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. 791 97

To identify a gene responsible for multiple endocrine neoplasia type 1 (MEN1), we attempted to isolate potentially transcribable fragments from cosmid clones derived from a region on chromosome 11q13 where genetic linkage studies and analyses of loss of heterozygosity in MEN1-associated tumors have localized the MEN1 gene. By an exon-amplification method, we recovered three exon-like sequences from one of these clones, cCI11-367, and using these sequences as probes we were able to isolate new clones from cerebrum, cerebellum, and fetal-liver cDNA libraries. Sequence analysis of these cDNA clones revealed that the transcribed gene, designated ZFM1, encodes a novel 623-amino-acid protein containing domains with interesting structural properties including a nuclear transport domain, a metal binding motif, and glutamine- and proline-rich regions. Analysis by the reverse-transcriptase polymerase chain reaction (RT-PCR) indicated that this gene is expressed in various tissues including endocrine organs such as thyroid gland, pancreas, adrenal gland, and ovary. These data suggest that ZFM1 might be a candidate for mutations that cause MEN1.
Hum Mol Genet 1994 Mar
PMID:Isolation and characterization of a novel gene encoding nuclear protein at a locus (D11S636) tightly linked to multiple endocrine neoplasia type 1 (MEN1). 791 30

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are two closely related cancer syndromes inherited in an autosomal dominant manner. Mutations in the RET proto-oncogene were found in MEN 2A and FMTC families. In this study we report seven different germline mutations in the RET proto-oncogene in five of five MEN 2A and five of six FMTC families. Each of the mutations involves a cysteine residue in the extracellular cysteine-rich domain of the RET receptor tyrosine kinase. We developed simple polymerase chain reaction based diagnostic tests for all seven mutations in these families.
Hum Mol Genet 1994 Apr
PMID:Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests. 791 65

We have designed PCR primers that permit the rapid non-isotopic detection of mutations in codon 634 of the RET proto-oncogene, the causative mutations in over 80% of MEN 2A and 50% of FMTC families. In this paper we report the investigation of eleven MEN 2A families referred to the East Anglian Regional Genetics Service. Nine of these families carry codon 634 mutations. We were able to confirm the diagnosis of MEN 2A in twenty six affected individuals and to determine the carrier status of forty one individuals thought to be at risk of developing the disease. Of those at risk, thirty one patients lacked the familial mutation and ten were presymptomatic carriers of MEN 2A. In five cases the direct test proved that patients who had been treated by thyroidectomy but who lacked confirmed cancer, did not carry the familial mutation, removing the perceived risk of MEN 2A from their children. This group included one patient who had been diagnosed as having mild C-cell hyperplasia, confirming that in MEN 2A families C-cell hyperplasia can result from causes other than the presence of the MEN 2A mutation.
Hum Mol Genet 1994 Apr
PMID:Direct, non-radioactive detection of mutations in multiple endocrine neoplasia type 2A families. 791 66

Since germline mutations in the RET proto-oncogene (RET) predisposing to tumor development in Familial Medullary Thyroid Carcinoma (FMTC), Multiple endocrine neoplasia type 2A (MEN 2A), and Multiple endocrine neoplasia type 2B (MEN 2B) were reported, it has become possible to identify gene carriers with a very high degree of accuracy. Mutations in FMTC and MEN 2A exclusively affect cysteine residues in exon 10 and 11 of RET, whereas in MEN 2B codon 918 in exon 16 is involved. This latter mutation has also been described in a subset of apparently sporadic medullary thyroid carcinomas (MTC). Mutations in MEN 2B often occur as de novo germline mutations, whereas de novo mutations have not yet been described in FMTC or MEN 2A. We analyzed ten MTC:s and ten pheochromocytomas, all clinically judged to be sporadically occurring, by direct DNA sequencing of exons 10, 11, and 16 of RET. This analysis revealed a de novo germline mutation of codon 634 in exon 11 in a patient with MTC. In addition, somatic mutations of codon 918 in exon 16 in six of the remaining MTC:s were found. Interestingly, the presence of this somatic mutation was associated with a significantly less favorable clinical outcome.
Hum Mol Genet 1994 Aug
PMID:Somatic and MEN 2A de novo mutations identified in the RET proto-oncogene by screening of sporadic MTC:s. 798 99

We have carried out genetic linkage analyses using fifteen polymorphic loci in the pericentromeric region of chromosome 10 in families with the inherited cancer syndromes multiple endocrine neoplasia (MEN) type 2A or 2B. A highly polymorphic microsatellite from the locus D10S141 in q11.2 was found to be recombinant with respect to the disease locus in two individuals and defines a new proximal flanking marker for both MEN2A and 2B. An additional recombination provides evidence that the locus D10S94, also in q11.2, is the closet distal flanking marker for MEN2A. This localises the MEN2A gene to a small region of 10q11.2 flanked by the loci D10S141 and D10S94, which are separated by a sex-averaged genetic distance of 0.55 cM. The MEN2B gene maps to a larger region, flanked by D10S141 and RBP3.
Hum Mol Genet 1993 Mar
PMID:Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2. 809 77

A YAC contig has been constructed spanning 1.1 Mb of human chromosome band 10q11.2 which encompasses three markers (D10S141, RET, D10S94) closely linked to the gene for MEN 2A. This physical linkage group is ordered cen-D10S141-RET-D10S94-qter, and must include MEN2A, which lies in a 480 kb region between flanking markers D10S141 and D10S94.
Hum Mol Genet 1993 Mar
PMID:Localisation of the gene for multiple endocrine neoplasia type 2A to a 480 kb region in chromosome band 10q11.2. 809 78

The FAU gene (FBR-MuSV associated ubiquitously expressed gene) encodes the ribosomal protein S30 fused with a Ubiquitin-like molecule. The FAU gene is expressed in a wide range of tissues, is evolutionarily conserved, and has putative tumour suppressor activity in vitro. The human FAU gene maps to the long arm of chromosome 11 band q13, close to the PYGM locus. This locus is tightly linked to the Multiple Endocrine Neoplasia type 1 (MEN1) locus. The FAU gene properties, together with its chromosomal localisation on 11q13, make it a candidate gene for MEN1. To test this hypothesis we screened 33 unrelated patients with MEN1 for constitutional genetic alterations in the FAU gene by Southern blot analysis, denaturing gradient gel electrophoresis (DGGE) and in two cases complemented by DNA sequencing to confirm the DGGE data. Furthermore, 10 parathyroid and pancreatic tumours from MEN1 patients and 15 each of sporadic parathyroid and pituitary tumours were similarly examined. In addition, we studied the expression of the FAU gene at the RNA level in 9 MEN1-associated tumours by Northern blot analysis. No FAU gene anomalies could be demonstrated by any of these techniques. We conclude that FAU is not likely to be the MEN1 tumour suppressor gene.
Hum Mol Genet 1993 Apr
PMID:Exclusion of FAU as the multiple endocrine neoplasia type 1 (MEN1) gene. 809 2

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.
Hum Mol Genet 1993 Jul
PMID:Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. 810 3

Ret is a receptor tyrosine kinase predominantly expressed in tissue derived from the neuroectoderm and is involved in multiple endocrine neoplasia type 2A and 2B, familiar medullary thyroid carcinoma, and Hirschsprung's disease. The ligand for the receptor is still unknown. Previously, using a human epidermal growth factor receptor - Ret chimaeric receptor (HERRet) stably transfected into fibroblasts, it was shown that Ret activation induces the activation of p21ras, but, surprisingly, activation of extracellular signal-regulated kinase 2 (ERK2) was not observed (Santoro et al. (1994) Mol. Cell. Biol., 14, 663). In this report we describe early signaling events induced by the activated HERRet fusion receptor in a cell line derived from neuroectodermal tissue, SK-N-MC. In these cells, activated HERRet induces tyrosine phosphorylation of Shc, complex formation of Shc with Grb2 and Sos and activation of p21ras. Importantly, also ERK2 is activated. This activation was strong and sustained for at least 2 h. Activation was abolished by the dominant negative p21rasasn17 mutant, showing that activation of ERK2 is mediated by p21ras. These results suggest that Ret can induce ERK2 activation in a p21ras dependent manner in cells derived from tissue where Ret is endogenously expressed.
 ...
PMID:Ret receptor tyrosine kinase activates extracellular signal-regulated kinase 2 in SK-N-MC cells. 857 Jan 70


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