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)

Vestibular schwannoma occurs both as a sporadic tumour and in the dominantly inherited familial cancer syndrome neurofibromatosis type 2 (NF2). The gene for NF2 has recently been isolated on chromosome 22, and the demonstration of inactivating germline mutations in NF2 patients and NF2 associated tumours suggests that it act as a tumour suppressor. We have investigated 85 sporadic and 2 NF2 associated vestibular schwannomas, and one vagal schwannoma for chromosome 22 allele loss and NF2 gene mutations. A further 7 vestibular schwannomas were investigated for NF2 mutations only. Chromosome 22 allele loss was detected in 34 of 87 vestibular schwannomas and in the vagal nerve schwannoma. Six exons of the NF2 gene were investigated by SSCP analysis in all 95 tumours. Somatic NF2 gene mutations were detected in 13 non-familial vestibular schwannomas and in one of the NF2 vestibular schwannomas. Seven non-familial tumours with an NF2 gene mutation also displayed a chromosome 22 allele loss. Thirteen of the mutations were predicted to produce truncation of the NF2 protein. These results suggest that somatic mutations of the NF2 tumour suppressor gene are a critical step in the pathogenesis of both familial and non-familial vestibular schwannoma and that the mechanism of tumourigenesis complies with a 'two-hit' mutation model.
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PMID:Somatic NF2 gene mutations in familial and non-familial vestibular schwannoma. 800 7

The recent identification of the NF2 tumour suppressor gene has enabled large scale screening for pathological mutations in the gene. We have sought germline mutations in the NF2 gene by SSCP and heteroduplex analysis of cDNA and genomic DNA samples followed by cloning and sequencing of mutant alleles. In the present report we describe 11 putative pathological mutations, including five nonsense mutations, three short insertions or deletions causing frameshifts and three missense mutations. Most stop mutations and frameshift mutations were found in individuals expressing a severe phenotype while one of the three missense mutations was associated with a mild phenotype. Four unrelated NF2 patients of the 93 tested were found to have identical nonsense mutations caused by a C to T transition (C169) in a CpG dinucleotide, which is a potential mutational hotspot in the NF2 tumour suppressor gene.
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PMID:Germline mutations in the neurofibromatosis type 2 tumour suppressor gene. 808 68

Meningiomas are common central nervous system tumours which present usually in the 4th and 5th decades of life. Loss of constitutional heterozygosity on chromosome 22 in 60% of sporadic meningiomas has implied the involvement of a tumour suppressor gene. The neurofibromatosis type 2 gene (NF2), a prime candidate for involvement in meningioma, was screened for point mutations. After examining eight of the 16 known NF2 exons in 151 meningiomas, 24 inactivating mutations were characterized. Significantly, these aberrations were exclusively detected in tumours which lost the other chromosome 22 allele. These results provide strong evidence that the suppressor gene on chromosome 22, frequently inactivated in meningioma, is the NF2 gene, and suggest that another gene is involved in the development of 40% of meningiomas.
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PMID:Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. 816 72

Neurofibromatosis type 2 (NF2) is a monogenic dominantly inherited disease predisposing carriers to develop nervous system tumours. To identify the genetic defect, the region between two flanking polymorphic markers on chromosome 22 was cloned and several genes identified. One is the site of germ-line mutations in NF2 patients and of somatic mutations in NF2-related tumours. Its deduced product has homology with proteins at the plasma membrane and cytoskeleton interface, a previously unknown site of action of tumour suppressor genes in humans.
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PMID:Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. 850 75

The cloning of the gene that causes neurofibromatosis type 2 (NF2), a hereditary tumour syndrome typically associated with brain tumours such as vestibular schwannomas and meningiomas, represents another successful application of the "positional cloning" approach--that is, the isolation of a hereditary disease gene of unknown function, based on the determination of its chromosomal location in the human genome. The NF2 gene is homologous to a family of genes whose products, including moesin, ezrin, radixin and protein 4.1, appear to have an important role in bridging the cell membrane and the intracellular cytoskeletion. Mutation analyses have revealed that the NF2 tumour suppressor gene is frequently mutated not only in vestibular schwannomas and meningiomas from NF2 patients, but also in their sporadic counterparts, which represent approximately one third of all human brain tumours. Furthermore, malignant human tumours seemingly unrelated to the NF2 syndrome, such as malignant melanomas (derived from the neural crest) and malignant mesotheliomas (derived from pleural mesoderm), also frequently have mutations or deletions at the NF2 locus, suggesting a broader role of the NF2 gene in the initiation and progression of human neoplasms.
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PMID:The neurofibromatosis 2 (NF2) tumour suppressor gene: implications beyond the hereditary tumour syndrome? 871 20

Neurofibromatosis 1 and 2 (NF1 and NF2) are autosomal dominantly inherited disorders with close to 100% penetrance. NF1 is one of the most frequent human genetic diseases with an incidence of 1:3000. The incidence of NF2 is about 10 fold lower. NF1 is caused by mutations which inactivate the NF1 gene on chromosome 17q, while the NF2 gene is on chromsome 22. Both genes are tumour suppressor genes. The product of the NF1 gene, called neurofibromin, is a large protein of 2818 amino acids. The protein acts as a negative regulator in the ras signal transduction pathway and may also act downstream of ras. In the cell types that are affected in NF1 patients, the absence of neurofibromin leads to increased proliferation resulting in benign, and in some cases malignant tumours. The product of the NF2 gene is a protein of 595 amino acids. The protein displays in its N-terminal half considerable homology with proteins that are involved in contacts between the cytoskeleton and the cell membrane, and a similar function has been proposed for the NF2 protein. How the absence of the NF2 protein may lead to the development of Schwannomas and meningiomas, which are the major manifestations of NF2 in patients, is not clear at present.
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PMID:Neurofibromatosis and associated tumour suppressor genes. 888 Aug 65

The ERM family consists of three closely related proteins, ezrin, radixin, and moesin, that are thought to work as cross-linkers between plasma membranes and actin-based cytoskeletons. Recent analyses of the structure and functions of ERM proteins have revealed that these molecules are involved not only in cytoskeletal organization but also in signal transduction. Furthermore, identification of the neurofibromatosis type 2 tumour suppressor, which shows striking sequence similarity to ERM proteins, has increased interest in this family.
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PMID:ERM (ezrin/radixin/moesin) family: from cytoskeleton to signal transduction. 901 73

Two forms of neurofibromatosis, type 1 (NF1) and type 2 (NF2) are connected with genes localized on chromosomes 17 and 22, respectively. The genes that are inactivated in neurofibromatosis code for the proteins neurofibromine and merline, respectively. Since inactivation leads to neoplasia, they are called tumour suppressor genes. Neurofibromine shows resemblances to proteins that serve to inactivate oncogenes. Merline has a relationship with proteins that connect the cytoskeleton and the cell membrane. The precise function of the proteins is still unknown. The NF1 gene is characterized by extraordinarily high sensitivity to mutation; half the NF1 patients have not inherited the disease. In the familial form of neurofibromatosis, a mutated gene is inherited and the normal allele in the tumour is inactivated, making tumour growth possible. In the sporadic form of neurofibromatosis, both normal alleles are inactivated locally in the tissue so that a tumour develops in that place.
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PMID:[Molecular-genetic aspects of neurofibromatosis]. 919 May 37

NF2 is the most commonly mutated gene in benign tumours of the human nervous system. The NF2 protein, called schwannomin or merlin, is absent in virtually all schwannomas, and many meningiomas and ependymomas. Using the yeast two-hybrid system, we identified betaII-spectrin (also known as fodrin) as a schwannomin-binding protein. Interaction occurred between the carboxy-terminal domain of schwannomin isoform 2 and the ankyrin-binding region of betaII-spectrin. Isoform 1 of schwannomin, in contrast, interacted weakly with betaII-spectrin, presumably because of its strong self-interaction. Thus, alternative splicing of NF2 may regulate betaII-spectrin binding. Schwannomin co-immunoprecipitated with betaII-spectrin at physiological concentrations. The two proteins interacted in vitro and co-localized in several target tissues and in STS26T cells. Three naturally occurring NF2 missense mutations showed reduced, but not absent, betaII-spectrin binding, suggesting an explanation for the milder phenotypes seen in patients with missense mutations. STS26T cells treated with NF2 antisense oligonucleotides showed alterations of the actin cytoskeleton. Schwannomin itself lacks the actin binding sites found in ezrin, radixin and moesin, suggesting that signalling to the actin cytoskeleton occurs via actin-binding sites on betaII-spectrin. Thus, schwannomin is a tumour suppressor directly involved in actin-cytoskeleton organization, which suggests that alterations in the cytoskeleton are an early event in the pathogenesis of some tumour types.
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PMID:Neurofibromatosis 2 tumour suppressor schwannomin interacts with betaII-spectrin. 953 18

Schwannomas are common benign tumours of schwann cell origin, frequently found in patients with neurofibromatosis type 2 (NF2). Inactivation of the NF2 tumour suppressor gene appears to be a molecular event responsible for the development of up to 60% of cases, but no data are available on other superimposed secondary or alternative molecular abnormalities in those schwannomas lacking NF2 gene inactivation. We analysed 23 sporadic schwannomas for mutations in the NF2 gene and for the allelic status at 1p, 14q and 22q, as alterations of these genomic regions appear to be related to tumour progression in meningiomas, another NF2-associated neoplasm. Nine samples displayed allelic losses for markers on chromosome 22, and deletions at 1p were detected in two. No case showed losses for 14q. Three tumours displayed NF2 gene mutations, at exons 2, 7 and 12. Our results confirm that inactivation of the NF2 gene is a primary event in schwannoma development, and provide data suggesting that allelic loss at 1p may contribute to the pathogenesis of a small subgroup of this histological tumour type.
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PMID:Allelic status of 1p, 14q, and 22q and NF2 gene mutations in sporadic schwannomas. 985 12


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