Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The MEN1 gene is considered to be a tumour suppressor gene and has been localised to a 1-Mb region of 11q13.1. In this study, we report the physical localisation of the 13-kDa FK506 and rapamycin binding protein gene (FKBP2) to the cosmid marker D11S750, which is located inside the MEN1 region of non-recombination. The product of this gene is involved in signal transduction and is thus a candidate cell growth regulator or tumour suppressor gene. Northern studies have revealed that FKBP2 is expressed in those tissues predisposed to hyperplasia in MEN1; however, single-strand conformation polymorphism analysis and direct sequencing of DNAs from affected members of MEN1 kindreds and sporadic tumour DNAs have been performed and no mutations have been found. These studies exclude FKBP2 as a candidate gene for MEN1.
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PMID:Exclusion of the 13-kDa rapamycin binding protein gene (FKBP2) as a candidate gene for multiple endocrine neoplasia type 1. 753 44

Primary hyperparathyroidism is a common disorder with an annual incidence of approximately 0.5 in 1,000 (ref. 1). In more than 95% of cases, the disease is caused by sporadic parathyroid adenoma or sporadic hyperplasia. Some cases are caused by inherited syndromes, such as multiple endocrine neoplasia type 1 (MEN1; ref. 2). In most cases, the molecular basis of parathyroid neoplasia is unknown. Parathyroid adenomas are usually monoclonal, suggesting that one important step in tumour development is a mutation in a progenitor cell. Approximately 30% of sporadic parathyroid tumours show loss of heterozygosity (LOH) for polymorphic markers on 11q13, the site of the MEN1 tumour suppressor gene. This raises the question of whether such sporadic parathyroid tumours are caused by sequential inactivation of both alleles of the MEN1 gene. We recently cloned the MEN1 gene and identified MEN1 germline mutations in fourteen of fifteen kindreds with familial MEN1 (ref. 10). We have studied parathyroid tumours not associated with MEN1 to determine whether somatic mutations in the MEN1 gene are present. Among 33 tumours we found somatic MEN1 gene mutation in 7, while the corresponding MEN1 germline sequence was normal in each patient. All tumours with MEN1 gene mutation showed LOH on 11q13, making the tumour cells hemi- or homozygous for the mutant allele. Thus, somatic MEN1 gene mutation for the mutant allele. Thus, somatic MEN1 gene mutation contributes to tumorigenesis in a substantial number of parathyroid tumours not associated with the MEN1 syndrome.
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PMID:Somatic mutation of the MEN1 gene in parathyroid tumours. 924 Dec 76

The search for the gene whose mutations predispose individuals to multiple endocrine neoplasia type 1 (MEN-1) started in 1988 when the MEN1 locus was assigned to 11q13, close to PYGM. It came to an end with the recent identification of a gene expressed ubiquitously which harbours inactivating mutations associated with MEN-1. During these nine years, the genetic linkage interval had been slowly reduced, and losses of heterozygosity (LOH) in MEN-1 tumours had given strong indications that MEN1 was a tumour suppressor gene. It is ironic that MEN1 was finally found to be located less than 100 kb telomeric to PYGM. From the beginning, this gene was the most tightly linked genetically to MEN-1. In addition, LOH had already shown (in 1990) that it was the most likely centromeric boundary of the MEN1 minimal region. We recently narrowed the critical region to 900 kb through meiotic mapping, and established a 1200-kb sequence-ready contig consisting of cosmids, bacterial artificial chromosomes (BACs) and P1-derived artificial chromosomes (PACs), including three gene clusters (19 genes and 3 expressed sequence tags). Taking LOH results into account, the gene was likely to be present in the 300-kb area telomeric to PYGM that we had covered with BACs. One of the novel genes that we have identified by cDNA selection in this region, SCG2 (Suppressor Candidate Gene 2), proved to be identical to the recently published MEN1 gene. Mutation analysis of SCG2 in 11 unrelated MEN-1 families identified one nucleotide sequence polymorphism and 10 different mutations that segregated with the disease.
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PMID:The search for the MEN1 gene. The European Consortium on MEN-1. 968 41

Dideoxyfingerprinting was used to screen for germline and somatic MEN1 mutations. This method, applied to a panel of germline DNA from 15 probands with multiple endocrine neoplasia type 1 (MEN-1), allowed confident discovery of the MEN1 gene. Germline MEN1 mutation has been found in 47 out of 50 probands with familial MEN-1, in 7 out of 8 cases with sporadic MEN-1, and in 1 out of 3 cases with atypical sporadic MEN-1. Germline MEN1 mutation was not found in any of five probands with familial hyperparathyroidism. Somatic MEN1 mutations were found in 7 out of 33 parathyroid tumours not associated with MEN-1. Allowing for repeating mutations, a total of 47 different germline or somatic MEN1 mutations have been identified. Most predict inactivation of the encoded 'menin' protein. supporting expectations that MEN1 is a tumour suppressor gene. The 16 observed missense mutations were distributed across the gene, suggesting that many domains are important to its as yet unknown functions.
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PMID:Germline and somatic mutation of the gene for multiple endocrine neoplasia type 1 (MEN1). 968 42

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominantly inherited cancer syndrome (OMIM 131100), with tumours in several endocrine glands. In 1997 the responsible tumour suppressor gene was identified and recently it was shown that menin, its encoded protein, represses JunD-activated gene expression. Although many MEN 1 patients have been investigated both clinically and genetically, no genotype-phenotype correlation has been found yet. The vast majority of MEN1 gene mutations involve point mutations. We describe a patient in whom a 26 base pair deletion in the MEN1 gene, comprising part of exon 3 and part of intron 3, causes activation of a cryptic donor splice site at the beginning of exon 3. This germline mutation results in an in frame deletion of 105 nucleotides in MEN1 gene mRNA, i.e. an internal deletion of 35 amino acids in the menin protein. Since the deleted region of menin has been implicated in binding to JunD, this may explain the tumourigenic effect of this mutation. The knowledge of this MEN1 gene germline defect, may be used for presymptomatic identification of MEN 1 disease gene-carriers among family-members of this proband. This enables early detection of tumour development, timely treatment and genetic counseling.
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PMID:Internally shortened menin protein as a consequence of alternative RNA splicing due to a germline deletion in the multiple endocrine neoplasia type 1 gene. 1081 10

MEN1 is a novel tumour suppressor gene involved in the etiology of sporadic endocrine pancreatic tumours. Based on common ontogenetic features of both tissues, we analyzed the role of MEN1 in ductal pancreatic cancer. Wild type MEN1 mRNA expression, but no mutations within the MEN1 coding sequence or MEN1 promoter region were detected in human pancreatic adenocarcinoma tissues and carcinoma cell lines, using sensitive single-strand conformational polymorphism-heteroduplex and sequencing analyses. Thus, human pancreatic cancer does not seem to require inactivation of the MEN1 tumour suppressor pathway.
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PMID:Role of the MEN1 tumour suppressor gene in human ductal pancreatic cancer. 1089 42

Endocrine tumours of the pancreas, anterior pituitary or parathyroids arise either sporadically in the general population, or as a part of inherited syndromes such as multiple endocrine neoplasia type 1 (MEN 1). The mechanisms responsible for the development of sporadic endocrine lesions are not well understood, although loss of heterozygosity (LOH) of the MEN1 locus on chromosome 11q13 and somatic mutation of the MEN1 gene have been frequently associated with the development of MEN 1-type sporadic endocrine lesions. To further investigate the role of the MEN1 gene in sporadic endocrine tumorigenesis, we analysed DNA from 14 primary parathyroid lesions, 8 anterior pituitary tumours and 3 pancreatic tumours for the presence of somatic MEN1 gene mutations and LOH of seven microsatellite markers flanking the MEN1 locus. In addition, we similarly analysed 8 secondary parathyroid lesions which arose in patients with chronic renal failure. None of the patients studied had a family history of MEN 1. Three primary parathyroid lesions and one pancreatic tumour (glucagonoma) were found to have lost one allele at the MEN1 locus. Somatic mutations were identified by SSCP and sequence analysis in one of these parathyroid lesions (P320L) and in the glucagonoma (E179V). These results support previous findings that inactivation of the MEN1 tumour suppressor gene contributes to the development of sporadic MEN 1-type endocrine lesions but is not associated with the development of parathyroid hyperplasia seen in some renal failure patients.
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PMID:Identification of somatic mutations of the MEN1 gene in sporadic endocrine tumours. 1099 46

Pituitary tumours are a common type of intracranial neoplasm and, depending on the cell type of origin, have diverse endocrine and reproductive effects. The developmental biology of the different cell types is understood to result from a sequential activation of a cascade of transcription factors, and mutations in these factors result in various forms of hypopituitarism. Tumours in the pituitary gland arise from activation of dominantly acting oncogenes such as gsp, or from loss of function of a series of tumour suppressor genes such as MEN1. Abnormal patterns of DNA methylation may be implicated in the allelic losses that cause tumour suppressor gene silencing. The different clinically recognized types of pituitary tumour are currently treated by medical therapies such as dopamine and somatostatin agonists, surgery or radiotherapy. However, these treatments are not entirely satisfactory and recent advances in gene therapy may offer valuable new therapeutic opportunities for patients with aggressive tumours that fail to respond to traditional approaches.
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PMID:Pituitary tumours. 1122 62

Loss of heterozygosity (LOH) studies have been used to identify sites harbouring tumour suppressor genes (TSGs) involved in tumour initiation or progression. To further elucidate the genetic mechanisms for follicular and papillary thyroid tumours development, we studied the frequency of LOH in 36 thyroid tumours (21 follicular thyroid adenomas (FAs) and 15 papillary thyroid carcinomas (PTCs)) on 10 specific genomic areas: 3p22, 3p25, 7q21, 7q31, 10q23, 10q25-26, 11q13, 11q23, 13q13 and 17p13.3-13.2 using 20 polymorphic markers. We have selected these areas for two reasons: (a) Even though LOH in thyroid neoplasms has been described in some of these areas, results are controversial, and (b) we have also studied areas described as involved in other epithelial or endocrine tumour types, but not studied up to now in thyroid neoplasms. Two areas showed a high percentage of LOH: 7q31 and 11q23. A 62% LOH was found at 7q31 in the FAs, suggesting, as other authors have proposed, that at least one TSG must be present in the vicinity of the c-met locus. The second area in frequency was at the 11q23 locus, with a 45% LOH in the FAs. This area was studied because it has been described as being involved in the development of epithelial and endocrine cancers. This locus had not been studied before in thyroid neoplasms. This result is interesting because the LOH11CR2A gene is localised at this locus. We suggest that this gene and/or an other TSG nearby may be involved in the progression to FA. In our study, a low percentage of LOH was found in the PTC samples, indicating that TSGs present in the areas we have studied are not significantly involved in their progression. Our data also suggest that TSGs located in areas where no LOH was detected (PTEN, MEN1, Cyclin D1, BRCA2 and RFC3) are not involved or do not have an important role in tumour progression.
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PMID:Screening of selected genomic areas potentially involved in thyroid neoplasms. 1172 Aug 45

The treatment of pituitary tumours strongly depends on their clinical presentation. In general, the treatment aims are reducing tumour volume and/or decreasing hormone hypersecretion. It relies on single or a combination of three different methods: surgery, medication and radiotherapy. The rationale for deciding the treatment are many but include the aggressiveness of the tumour. The aetiologies of sporadic pituitary adenomas are not fully understood. However, several causes have been identified resulting in specific familial phenotypes like multiple endocrine neoplasia type I (MEN1). MEN1 is related to mutations in the MEN1 gene, a tumour suppressor gene localized on chromosome 11q13 and which encodes menin, a 610 amino acid protein. During the last years, an evidence progressively emerged that MEN1-related adenomas were more aggressive and less responsive to therapy than their sporadic counterparts. In this article, we review the differences between sporadic and MEN1-related adenomas and suggest specific ways of treatment and follow-up for MEN1-related tumours.
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PMID:The treatment of sporadic versus MEN1-related pituitary adenomas. 1275 55


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