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)

Neurological tumours are common neoplasms of both adults and children. Recent studies have begun to delineate the genetic abnormalities that underlie such tumours, and have implicated two classes of genes, oncogenes and tumour suppressor genes. Most investigations have focused on those astrocytomas that affect the cerebral hemispheres of adults, since these are the most common and malignant brain tumours. The high-grade astrocytomas that affect adults, such as glioblastoma multiforme, often have amplification of the epidermal growth factor receptor (EGFR) oncogene and loss of a variety of chromosomal loci that probably harbour tumour suppressor genes. Of the various tumour suppressor gene loci, the p53 gene on chromosome 17p has been studied most closely and has been shown to be mutated in both low- and high-grade astrocytomas. These genetic alterations may provide a means for subdividing astrocytomas into diagnostic categories. For instance, p53 gene mutations occur more commonly in glioblastomas from young adults and women, while EGFR gene amplification is more common in glioblastomas from older adults and men. For the other primary CNS tumours, genetic studies remain in their infancy. The neurocutaneous syndromes, such as neurofibromatosis types 1 and 2, have provided unique insights into neurological oncogenesis. The NF1 gene on chromosomes 17q and its product, neurofibromin, may be important in the formation of neurofibrosarcomas, while the NF2 gene on chromosome 22q and its product, merlin, are probably involved in the formation of schwannomas and other nervous system tumours. The further characterization of these and other neurological tumour genes will undoubtedly illuminate many other areas in neurooncology.
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PMID:Genetic basis of neurological tumours. 795 51

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

Ezrin, radixin, moesin and merlin form a subfamily of conserved proteins in the band 4.1 superfamily. The function of these proteins is to link the plasma membrane to the actin cytoskeleton. Merlin is defective or absent in schwannomas and meningiomas and has been suggested to function as a tumour suppressor. In this study, we have examined the role of ezrin as a potential regulator of the adhesive and invasive behaviour of tumour cells. We have shown that following inhibition of ezrin expression in colo-rectal cancer cells using antisense oligonucleotides, these cells displayed a reduced cell-cell adhesiveness together with a gain in their motile and invasive behaviour. These cells also displayed increased spreading over matrix-coated surfaces. Immunofluorescence studies revealed that antisense-treated cells also displayed an increased staining of paxillin in areas representing focal adhesions. Furthermore, coprecipitation studies revealed an association of ezrin with E-cadherin and beta-catenin. Induction of the phosphorylation of ezrin by orthovanadate and hepatocyte growth factor/scatter factor resulted in changes similar to those seen with antisense treatment, together with a marked decrease in the association of ezrin with both beta-catenin and E-cadherin. It is concluded that ezrin regulates cell-cell and cell-matrix adhesion, by interacting with cell adhesion molecules E-cadherin and beta-catenin, and may thus play an important role in the control of adhesion and invasiveness of cancer cells.
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PMID:Ezrin regulates cell-cell and cell-matrix adhesion, a possible role with E-cadherin/beta-catenin. 1046 24

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

In Drosophila, the formation of the embryonic axes is initiated by Gurken, a transforming growth factor alpha signal from the oocyte to the posterior follicle cells, and an unknown polarising signal back to the oocyte. We report that Drosophila Merlin is specifically required only within the posterior follicle cells to initiate axis formation. Merlin mutants show defects in nuclear migration and mRNA localisation in the oocyte. Merlin is not required to specify posterior follicle cell identity in response to the Gurken signal from the oocyte, but is required for the unknown polarising signal back to the oocyte. Merlin is also required non-autonomously, only in follicle cells that have received the Gurken signal, to maintain cell polarity and limit proliferation, but is not required in embryos and larvae. These results are consistent with the fact that human Merlin is encoded by the gene for the tumour suppressor neurofibromatosis-2 and is a member of the Ezrin-Radixin-Moesin family of proteins that link actin to transmembrane proteins. We propose that Merlin acts in response to the Gurken signal by apically targeting the signal that initiates axis specification in the oocyte.
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PMID:Merlin, the Drosophila homologue of neurofibromatosis-2, is specifically required in posterior follicle cells for axis formation in the oocyte. 1117 92

The neurofibromatosis 2 protein product merlin, named for its relatedness to the ezrin, radixin and moesin (ERM) family of proteins, is a tumour suppressor whose absence results in the occurrence of multiple tumours of the nervous system, particularly schwannomas and meningiomas. Merlin's similarity to ERMs suggests that it might share functions, acting as a link between cytoskeletal components and the cell membrane. The N-terminus of merlin has strong sequence identity to the N-terminal actin-binding region of ezrin; here we describe in detail the merlin-actin interaction. Employing standard actin co-sedimentation assays, we have determined that merlin isoform 2 binds F-actin with an apparent binding constant of 3.6 microM and a stoichiometry of 1 mol of merlin per 11.5 mol of actin in filaments at saturation. Further, solid-phase binding assays reveal that merlin isoforms 1 and 2 bind actin filaments differentially, suggesting that the intramolecular interactions in isoform 1 might hinder its ability to bind actin. However, merlin does not bind G-actin. Studies of actin filament dynamics show that merlin slows filament disassembly with no influence on the assembly rate, indicating that merlin binds along actin filament lengths. This conclusion is supported by electron microscopy, which demonstrates that merlin binds periodically along cytoskeletal actin filaments. Comparison of these findings with those reported for ERM proteins reveal a distinct role for merlin in actin filament dynamics.
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PMID:The neurofibromatosis 2 protein product merlin selectively binds F-actin but not G-actin, and stabilizes the filaments through a lateral association. 1136 64

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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