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)

Ependymomas are glial tumours of the brain and spinal cord. The most frequent genetic change in sporadic ependymoma is monosomy 22, suggesting the presence of an ependymoma tumour suppressor gene on that chromosome. Clustering of ependymomas has been reported to occur in some families. From an earlier study in a family in which four cousins developed an ependymoma, we concluded that an ependymoma-susceptibility gene, which is not the NF2 gene in 22q12, might be located on chromosome 22. To localize that gene, we performed a segregation analysis with chromosome 22 markers in this family. This analysis revealed that the susceptibility gene may be located proximal to marker D22S941 in 22pter-22q11.2. Comparative genomic hybridization showed that monosomy 22 was the sole detectable genetic aberration in the tumour of one of the patients. Loss of heterozygosity studies in that tumour revealed that, in accordance to Knudson's two-hit theory of tumorigenesis, the lost chromosome 22 originated from the parent presumed to have contributed the wild-type allele of the susceptibility gene. Thus, our segregation and tumour studies collectively indicate that an ependymoma tumour suppressor gene may be present in region 22pter-22q11.2.
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PMID:Evidence for an ependymoma tumour suppressor gene in chromosome region 22pter-22q11.2. 1058 75

Meningiomas are common primary brain tumours frequently presenting with deleted and/or mutated NF2 gene located on 22q.1p has been reported as the second most commonly deleted chromosomal region in these neoplasms. A new member of the INK4 family of CDK inhibitors, the p18INK4c gene, has recently been mapped to this chromosomal arm. By virtue of its structural and functional similarities with the p16 gene, p18 has been implicated as a tumour suppressor gene in a variety of cancers. In this paper 40 human meningiomas were analysed for loss of heterozygosity (LOH) at the p18 locus, mutations and inactivating methylation of the p18 gene. LOH at D1S193, D1S463 and D1S211 microsatellite marker loci mapped to 1p32 was detected in 13 of 35 (37%), four of 20 (20%), and six of 24 (25%) tumour samples, respectively. One sample presented with homozygous deletion at D1S193. Mutational analysis using single stranded conformational polymorphism (SSCP) and direct sequencing did not detect any missense mutation but revealed a novel silent mutation, G to T, at coding nucleotide 435. Analysis of HgaI, BsaHI, ScrFI and Eco0109I restriction sites of p18 exon 1 revealed absence of inactivating methylation. Immunohistochemistry with p18 monoclonal antibody detected presence of cytoplasmic p18 staining in 21 of 22 examined samples. One sample did not stain and was shown to carry homozygous deletion at D1S193. Despite the high frequency of LOH at 1p32 microsatellite markers, the lack of genetic and epigenetic aberrations in the p18 gene together with the presence of p18 protein in all but one meningioma samples argues against the role of p18 as a tumour suppressor gene important for meningioma development.
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PMID:Molecular analysis of alterations of the p18INK4c gene in human meningiomas. 1073 68

Type 2 neurofibromatosis (NF2) is a dominantly inherited disorder characterized by a predisposition to multiple tumours of the nervous system. The incidence in the Caucasian population is estimated between one in 35,000 and one in 40,000 of live births. The NF2 gene was isolated and shown to have mutations in NF2 patients. It is considered to belong to tumour suppressor gene family. Direct NF2 gene analysis enables verification of tentative clinical diagnosis and makes genetic counselling possible.
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PMID:[Neurofibromatosis type 2 (NF2)--classical example of a rare familial cancer syndrome]. 1091 Jun 38

Neurofibromatosis type 2 is an often devastating autosomal dominant disorder which, until relatively recently, was confused with its more common namesake neurofibromatosis type 1. Subjects who inherit a mutated allele of the NF2 gene inevitably develop schwannomas, affecting particularly the superior vestibular branch of the 8th cranial nerve, usually bilaterally. Meningiomas and other benign central nervous system tumours such as ependymomas are other common features. Much of the morbidity from these tumours results from their treatment. It is now possible to identify the NF2 mutation in most families, although about 20% of apparently sporadic cases are actually mosaic for their mutation. As a classical tumour suppressor, inactivation of the NF2 gene product, merlin/schwannomin, leads to the development of both NF2 associated and sporadic tumours. Merlin/schwannomin associates with proteins at the cell cytoskeleton near the plasma membrane and it inhibits cell proliferation, adhesion, and migration.
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PMID:Neurofibromatosis type 2. 1110 52

Neurofibromatosis type 2 (NF2) is a dominantly inherited disease characterized by the formation of bilateral acoustic schwannomas and other benign tumours associated with the central nervous system. The NF2 protein, also known as merlin or schwannomin, is a recently cloned tumour suppressor and is mutated or inactivated in most schwannomas and meningiomas. Homology analysis indicates that merlin is most closely related to members of the protein 4.1 superfamily especially ezrin, radixin and moesin, the ERM proteins. ERM proteins link membrane proteins to the cytoskeleton. It has been speculated that disruption of a similar membrane-linking role for merlin is involved in the development of tumours. This review focuses on what is now known of the organization and role of merlin's functional domains and how its activity might be regulated. Recent evidence of post-translational regulatory mechanisms which offer hope for new drug intervention strategies to help alleviate this debilitating disease are asses sed.
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PMID:The tumour suppressor protein NF2/merlin: the puzzle continues. 1114 74

Rhabdoid tumours have been shown to carry somatic mutations in the INI1 (SMARCB1/hSNF5) gene. A considerable fraction of these tumours exhibit allelic losses on chromosome 22. Allelic loss on 22q also is characteristic for meningiomas, however most of these alterations are considered to be associated with mutations of the NF2 gene. We examined a series of 126 meningiomas for alterations in the INI1 gene. Four identical somatic mutations in exon 9 were detected resulting in an exchange of Arg to His in position 377 of INI1. Our observations were reproduced both by using DNA from a new round of extraction and by employing overlapping primers. This mutational hotspot therefore appears to be an important target in the formation of a fraction of meningiomas. In addition, 4 novel polymorphisms of INI1 were characterized. Our data indicate that the INI1 is a second tumour suppressor gene on chromosome 22 that may be important for the genesis of meningiomas.
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PMID:INI1 mutations in meningiomas at a potential hotspot in exon 9. 1116 77

In approximately 60% of sporadic meningiomas, the tumour suppressor gene NF2, located on chromosome 22q, is inactivated. Mutations in the NF2 gene have been specifically reported in transitional and fibrous, but not meningothelial, meningiomas. Since meningothelial meningiomas frequently occur in anterior parts of the skull base, the association between tumour localization, size, histological subtype and NF2 status was investigated in a group of 42 sporadic meningiomas. NF2 status was determined by LOH analysis, karyotyping and FISH. Tumour size and site were evaluated by CT scans and MRIs. A strong correlation between tumour localization in the anterior skull base and intact 22q was revealed (p=0.003). On the other hand, tumour localization at the convexity was associated with disruption of NF2 (p=0.023). Furthermore, an association between chromosome 22 status and histological subtype was observed: abnormalities of chromosome 22q were more frequent in transitional and fibrous meningiomas than in the meningothelial variant (p<0.001). Also, the meningothelial meningiomas were more often located in the anterior skull base (p<0.006). Based on these findings, it is concluded that an alternative histogenesis and genetic pathway is likely to exist for meningiomas arising in the anterior skull base.
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PMID:NF2 status of meningiomas is associated with tumour localization and histology. 1143 70

The mechanism underlying the tumour-suppressor activity of the neurofibromatosis type 2 (NF2) gene product, merlin, is largely undefined but there is evidence that the biological function of the protein might be mediated partly through interactions with the cytoskeleton. Merlin is expressed predominantly as two isoforms that differ at their C-termini owing to alternative splicing of exon 16. By expressing merlin isoform I as bait in a yeast two-hybrid screen, we isolated a clone encoding a region of the cytoskeletal protein beta-fodrin. Confirmation of the merlin-fodrin interaction was provided by using the mammalian two-hybrid system and binding assays in vitro. In addition, these assays and co-immunoprecipitation from mammalian cells revealed that the binding site for fodrin is located in the C-terminal half of merlin at a site that is masked in the native protein. Co-expression of the N-terminus of merlin decreased the interaction of its C-terminus with fodrin, implicating homophilic interactions of merlin isoform I in masking the fodrin-binding site. The effect of three disease-associated mutations on the merlin-fodrin interaction and merlin dimerization was also investigated. The mutation L535P, but not L360P or K413E, significantly decreased the merlin-fodrin interaction but not dimerization, indicating that the tumour suppressor ability of merlin might reside partly in its ability to interact with the cytoskeleton via fodrin.
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PMID:Binding of the merlin-I product of the neurofibromatosis type 2 tumour suppressor gene to a novel site in beta-fodrin is regulated by association between merlin domains. 1153 33

Mutations in both alleles of the tumour suppressor gene coding for merlin/schwannomin, an ERM family protein, cause the hereditary disease neurofibromatosis type 2 (NF2). NF2 is characterized by the development of multiple nervous system tumours especially vestibular schwannomas. Efficient oncoretrovirus-mediated gene transfer of different merlin constructs was used to stably re-express wild-type merlin in primary cells derived from human schwannomas. Using two-parameter FACS analysis we show that expression of wild-type merlin in NF2 cells led to significant reduction of proliferation and G0/G1 arrest in transduced schwannoma cells. In addition, we show increased apoptosis of schwannoma cells transduced with wild-type merlin. Our findings in primary schwannoma cells from NF2 patients strongly support the hypothesis of merlin acting as a tumour suppressor and may help in understanding development of human schwannomas in NF2.
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PMID:Transduction of wild-type merlin into human schwannoma cells decreases schwannoma cell growth and induces apoptosis. 1177

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder characterized by the occurrence of bilateral vestibular schwannomas, various brain and spinal tumours as well as peripheral nerve tumours, cutaneous tumours and juvenile posterior lenticular opacity. NF2 is caused by mutations in both alleles of a tumour suppressor gene coding for a protein called schwannomin or merlin. It is suggested that the development of NF2 tumours is caused by complete inactivation of the merlin/schwannomin gene. Interestingly, in a NF2 mouse model, peripheral nerve pathology was more frequently described than schwannomas. However, review of the literature shows that patients suffering from NF2 seldom have unexplained clinical features of peripheral nerve lesion unrelated to tumour masses. Single case reports describe sural nerve biopsies, which histologically show onion-bulb-like formations, seemingly originating from Schwann cells. We have conducted a systematic investigation to determine the occurrence and aetiology of peripheral nerve involvement in NF2 patients. We investigated 15 patients with definite NF2 and in 10 of these found electrophysiological evidence of neuropathy. In this study we present the classification of neuropathy, correlation to clinical findings, and histological findings of a sural nerve biopsy. We conclude that peripheral neuropathy, mostly of axonal type, is a common clinical finding in NF2. We hypothesize that the aetiology of this frequent peripheral neuropathy syndrome in NF2 is caused by compression effects of multiple tumourlets, originating along the length of the peripheral nerves on adjacent nerve fibres, by local influences of the endoneurial pathological cells on adjacent nerve fibres and/or the inability of these cells to properly adhere to, or ensheath, the axon.
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PMID:Occurrence and characterization of peripheral nerve involvement in neurofibromatosis type 2. 1196 Aug 90


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