Schwann cell hyperplasia and tumors in transgenic mice expressing a naturally occurring mutant NF2 protein

Giovannini, Marco; Robanus-Maandag, Els C.; Niwa‐Kawakita, Michiko; Valk, Martin van der; Woodruff, James M.; Goutebroze, Laurence; Merel, P.; Berns, Anton; Thomas, Gilles

doi:10.1101/gad.13.8.978

Cited by 141 publications

(148 citation statements)

References 32 publications

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“…Remarkably, vascular endothelial growth factor (VEGF) levels are significantly higher in pleural effusions secondary to mesothelioma in comparison with nonmalignant effusions (Zebrowski et al, 1999), and mesothelial cells and malignant mesothelioma cells have been reported as a source of VEGF (Lee et al, 2002). Heterozygous mutant Nf2 mice mainly develop osteogenic tumours (McClatchey et al, 1998) and only one mesothelioma was observed in a group of 16 Nf2 KO3/ þ mice (Giovannini et al, 2000). All tumour types found in these mice showed loss of the WT Nf2 allele.…”

Section: Discussionmentioning

confidence: 99%

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%

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

et al. 2003

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“…Briefly, in the first model, the floxed Nf2 gene was conditionally inactivated in SCs in vivo by tissue-specific expression of the Cre recombinase under the control of the P0 promoter (Giovannini et al, 2000). In the second model, SCspecific P0 promoter was used to drive the expression of a dominant negative mutant merlin (Sch-D39-121) (Giovannini et al, 1999). This model was used for experiments involving extracts from sciatic nerves.…”

Section: Mouse Modelsmentioning

confidence: 99%

Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas

et al. 2008

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The NF2 gene product, merlin/schwannomin, is a cytoskeleton organizer with unique growth-inhibiting activity in specific cell types. A narrow spectrum of tumors is associated with NF2 deficiency, mainly schwannomas and meningiomas, suggesting cell-specific mechanisms of growth control. We have investigated merlin function in mouse Schwann cells (SCs). We found that merlin regulates contact inhibition of proliferation by limiting the delivery of several growth factor receptors at the plasma membrane of primary SCs. Notably, upon cellto-cell contact, merlin downregulates the membrane levels of ErbB2 and ErbB3, thus inhibiting the activity of the downstream mitogenic signaling pathways protein kinase B and mitogen-activated protein kinase. Consequently, loss of merlin activity is associated with elevated levels of ErbB receptors in primary SCs. We also observed accumulation of growth factor receptors such as ErbB2 and 3, insulin-like growth factor 1 receptor and plateletderived growth factor receptor in peripheral nerves of Nf2-mutant mice and in human NF2 schwannomas, suggesting that this mechanism could play an important role in tumorigenesis.

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“…CD44 and ezrin play important roles in promoting tumor metastasis (Yu et al, 1997;Stamenkovic 1999, 2000;Yu et al, 2004;Khanna et al, 2001Khanna et al, , 2004, whereas merlin acts as a tumor suppressor (Rouleau et al, 1993;Trofatter et al, 1993;Lutchman and Rouleau, 1995;Sherman et al, 1997;McClatchey et al, 1998;Giovannini et al, 1999Giovannini et al, , 2000. Thus far, the functional relationship between CD44 and merlin and the manner in which CD44 affects the tumor-suppressing activity of merlin have not been established.…”

Section: Increased Expression Of Merlin Inhibits the Binding Of Fluormentioning

confidence: 99%

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

Bai

et al. 2006

Oncogene

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Mutation or loss of expression of merlin is responsible for neurofibromatosis type 2 (NF2), which is characterized by the development of schwannomas and other tumors of the nervous system. Like the ERM (ezrin-radixin-moesin) proteins, merlin interacts with CD44, a cell-surface receptor for hyaluronan (HA) that promotes tumorigenesis. However, the relationship between merlin and CD44 and the mechanism by which merlin exerts its tumorsuppressor function have not been elucidated. In the present study, we show that increased expression of wildtype merlin in Tr6BC1 schwannoma cells inhibits HA binding to CD44. Furthermore, we demonstrate that the residues required for this inhibitory effect and the interaction between CD44 and merlin lie within the first 50 amino acids of merlin. Overexpression of merlin inhibited subcutaneous growth of Tr6BC1 cells in immunocompromised Rag1 mice. In contrast, knocking down expression of endogenous merlin promoted tumor cell growth, as did overexpression of a merlin deletion mutant (merlinDel-1) that lacks the first 50 amino acids but not of other NH 2 -terminal deletion mutants. Together, our results demonstrate that inhibition of the CD44-HA interaction contributes to the tumor-suppressor function of merlin, and they suggest that merlin inhibits tumor growth, at least in part, by negatively regulating CD44 function.

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Schwann cell hyperplasia and tumors in transgenic mice expressing a naturally occurring mutant NF2 protein

Cited by 141 publications

References 32 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

Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

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