Heterogeneity of mesothelioma cell lines as defined by altered genomic structure and expression of theNF2 gene

Deguen, Brigitte; Goutebroze, Laurence; Giovannini, Marco; Boisson, Cécile; Neut, Ronald van der; Jaurand, Marie‐Claude; Thomas, Gilles

doi:10.1002/(sici)1097-0215(19980812)77:4<554::aid-ijc14>3.0.co;2-6

Cited by 52 publications

(44 citation statements)

References 22 publications

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“…The tumour suppressor gene, NF2, has been found to be frequently inactivated in mesothelioma (Bianchi et al, 1995;Sekido et al, 1995;Deguen et al, 1998), indicating that the deregulation of the NF2 pathway can be involved in the neoplastic transformation of mesothelial cells. Mesothelioma is not a characteristic feature of NF2 patients, but one case of peritoneal mesothelioma in an NF2 patient exposed to asbestos has been recently reported (Baser et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours

et al. 2003

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Biallelic NF2 gene inactivation is frequently found in human malignant mesothelioma. In order to assess whether NF2 hemizygosity may enhance susceptibility to asbestos fibres, we investigated the Nf2 status in mesothelioma developed in mice presenting a heterozygous mutation of the Nf2 gene (Nf2 KO3/ þ ), after intraperitoneal inoculation of crocidolite fibres. Asbestos-exposed Nf2 KO3/ þ mice developed tumoural ascites and mesothelioma at a higher frequency than their wild-type (WT) counterparts (Po0.05). Six out of seven mesothelioma cell lines established from neoplastic ascitic fluids of Nf2 KO3/ þ mice exhibited loss of the WT Nf2 allele and no neurofibromatosis type 2 protein expression was found in these cells. The results show the importance of the NF2 gene in mesothelial oncogenesis, the potential association of asbestos exposure and tumour suppressor gene inactivation, and suggest that NF2 gene mutation may be a susceptibility factor to asbestos.

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Section: Discussionmentioning

confidence: 99%

“…Positive controls for NF2 expression studies were total protein extracts from WT or Nf2 KO3/ þ mouse brain, whereas total protein extracts from a human mesothelioma cell line, CORO, established in the laboratory (Deguen et al, 1998), were used as negative control.…”

Section: Western Blot and Immunoprecipitation Analysesmentioning

confidence: 99%

Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours

et al. 2003

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“…12 and references therein). Mutations that lead to the skipping of exon 3 (Sch⌬81-121) or exons 2-3 (Sch⌬39 -121) have been observed in the germ line or in the tumors of the NF2 patients (12,18,19). These mutations impair the proper folding of the schwannomin FERM domain (7).…”

Section: Neurofibromatosis Type 2 (Nf2)mentioning

confidence: 99%

“…In human tumors, levels of mutant Sch are consistently below limits of detection although NF2 mutant alleles were detected at the mRNA level (12)(13)(14)(15). Therefore, we reasoned that mutant schwannomin might be degraded quickly.…”

Section: Neurofibromatosis Type 2 (Nf2)mentioning

confidence: 99%

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Mutant Products of the NF2 Tumor Suppressor Gene Are Degraded by the Ubiquitin-Proteasome Pathway

Gautreau¹,

Manent²,

Fiévet³

et al. 2002

Journal of Biological Chemistry

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Neurofibromatosis type 2 (NF2), a syndrome associated with multiple tumors of the nervous system, mostly schwannomas, is caused by mutations in the NF2 tumor suppressor gene that encodes schwannomin (Sch). Here we examined NF2 pathogenetic mutations that result in misfolding of the FERM domain. We found that these mutant forms of Sch were efficiently degraded by the ubiquitin-proteasome pathway. In transfected cells, Sch⌬F118 was 3-fold more efficiently degraded than the related molecule ezrin bearing the equivalent mutation. In heterozygous Nf2 knock-out mouse fibroblasts, endogenous mutant Sch⌬81-121, but not wild type Sch, was also degraded by proteasomes. We further show that this degradation pathway is functional in primary Schwann cells. We analyzed Sch⌬39 -121 expressed in a transgenic mouse model of NF2 and found that Sch⌬39 -121, but not the endogenous wild type Sch, was unstable due to proteasome-mediated degradation. Altogether these results suggest that degradation of mutant Sch mediated by the ubiquitin-proteasome pathway is a physiopathological pathway contributing to the loss of Sch function in NF2 patients. Neurofibromatosis type 2 (NF2)1 is a dominantly inherited disorder characterized by the predisposition to develop multiple nervous system tumors, in particular schwannomas. Tumor development in NF2 patients is in accordance with Knudson's two-hit hypothesis for tumor suppressor genes. As NF2 patients inherit one mutant NF2 allele, a second hit in the remaining wild type allele is sufficient to induce tumorigenesis. The two NF2 alleles are also inactivated in the majority of sporadic schwannomas (1).The NF2 tumor suppressor gene product, Schwannomin (Sch), also known as merlin, displays 45% identity with ERM proteins, which are cytoskeletal linkers between cortical actin filaments and the plasma membrane (2, 3). Like ERM proteins, Sch has an amino-terminal FERM domain and a carboxylterminal domain that associate in an intramolecular manner to form closed monomers and in an intermolecular manner to form oligomers (4 -6). The FERM domain of Sch binds to the plasma membrane and to filamentous actin (7,8). Sch regulates cell adhesion and motility (9, 10) and mediates contact inhibition (11).In human tumors, levels of mutant Sch are consistently below limits of detection although NF2 mutant alleles were detected at the mRNA level (12-15). Therefore, we reasoned that mutant schwannomin might be degraded quickly. To examine this hypothesis, we studied the stability of mutant schwannomin in transfected cells or in primary cultures derived from mouse models developed to examine the pathogenesis of NF2 (16, 17). We focused on pathogenetic mutations in the conserved FERM domain of Sch. The deletion of the phenylalanine 118 codon in exon 3 has been described in two unrelated families affected by NF2 as well as in a sporadic meningioma (Ref. 12 and references therein). Mutations that lead to the skipping of exon 3 (Sch⌬81-121) or exons 2-3 (Sch⌬39 -121) have been observed in the germ line or in the tumors o...

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Gene expression profiling of malignant mesothelioma cell lines: cDNA array study

et al. 2001

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To reveal genes relevant for malignant mesothelioma (MM), we carried out cDNA array experiments on 4 MM cell lines and 2 primary mesothelial cell cultures established from pleural fluid of non‐cancer patients. Human cancer gene filters including 588 genes were used for the cDNA array experiments. Our study revealed 26 over‐expressed genes that play a role in the regulation of cell fate, cell cycle, cell growth and DNA damage repair and 13 under‐expressed genes encoding growth factors, receptors and proteins involved in cell adhesion, motility and invasion to be common to 3 or 4 MM cell lines. We confirmed the cDNA array results using RT‐PCR for 5 of the over‐expressed genes and for 3 of the under‐expressed genes. Our study presents gene expression profiles in MM cell lines and shows the involvement of several genes, such as those encoding JAGGED1, ser/thr protein kinase NIK, Ku80 and cyclin D2, novel in MM. © 2001 Wiley‐Liss, Inc.

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Heterogeneity of mesothelioma cell lines as defined by altered genomic structure and expression of theNF2 gene

Cited by 52 publications

References 22 publications

Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours

Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours

Mutant Products of the NF2 Tumor Suppressor Gene Are Degraded by the Ubiquitin-Proteasome Pathway

Gene expression profiling of malignant mesothelioma cell lines: cDNA array study

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