Overexpression of activated neu/erbB2 initiates immortalization and malignant transformation of immature Schwann cells in vitro

Sherman, Larry S.; Sleeman, Jonathan P.; Hennigan, Robert F.; Herrlich, Peter; Ratner, Nancy

doi:10.1038/sj.onc.1203055

Cited by 16 publications

(11 citation statements)

References 49 publications

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“…We have also presented strong evidence that ErbB-mediated activation of downstream mitogenic signaling pathways is important for schwannoma development. In vitro, expression of a constitutively activated form of ErbB2 in rat SC promotes transformation (Sherman et al, 1999). In vivo, chemically induced activating mutations of ErbB2 trigger malignant schwannoma development in rodents (Nikitin et al, 1991;Buzard et al, 1999).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Anyhow, early biallelic loss of Nf2 function in neural crest-derived cells of the P0Cre;Nf2 flox2/flox2 ;p53 þ /À mice shifts the tumour spectrum from osteogenic to peripheral nerve sheath tumours. Although it has been demonstrated that the developmental stage of Schwann cells may determine their susceptibility to tumour-initiating alterations (Jin et al, 1993;Sherman et al, 1999), a concomitant modification of the tumour spectrum has not been described yet.…”

Section: Also P0crementioning

confidence: 99%

Synergy of Nf2 and p53 mutations in development of malignant tumours of neural crest origin

et al. 2004

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Previously, we have mimicked human neurofibromatosis type 2 (NF2) in conditional Nf2 mutant (P0Cre;Nf2 flox2/flox2 ) mice. Schwannomas, characteristic for NF2, were found at low frequency in older mice. Here, we report that these mice, upon additional hemizygosity for p53, rapidly develop multiple tumours showing features consistent with malignant peripheral nerve sheath tumours. Thus, p53 hemizygosity promotes tumorigenesis of mutant Nf2 peripheral nerve cells. In contrast, young P0Cre;Nf2 flox2/ þ ;p53 þ /À cis mice mainly succumb to Nf2/p53-related osteogenic tumours. Therefore, Cre-mediated early biallelic loss of Nf2 function in neural crest-derived cells hemizygous for p53 results in resistance to osteogenic tumours and increased susceptibility to peripheral nerve sheath tumours. Keywords: MPNST; neural crest; P0 promoter; conditional knockout mice; compensatory signalling Introduction Vestibular schwannomas are benign neural sheath tumours of the vestibular branch of the eighth cranial nerve. They occur either as bilateral tumours, the hallmark of the human hereditary cancer syndrome neurofibromatosis type 2 (NF2), or as sporadic unilateral tumours. Loss or mutational inactivation of both alleles of the NF2 gene in the Schwann cell is the ratelimiting step in neoplastic transformation. NF2 patients carrying one mutant NF2 allele are predisposed not only to bilateral vestibular schwannomas but also to schwannomas of other cranial, spinal and cutaneous nerves, to cranial and spinal meningiomas, as well as to presenile lens opacities and cerebral calcifications (McKusick, 1994). Loss of NF2 function is also frequently found in mesotheliomas (Bianchi et al., 1995). The product of the NF2 gene, called schwannomin or merlin (Rouleau et al., 1993;Trofatter et al., 1993), has structural similarity with members of the ezrin-radixin-moesin (ERM) family of proteins that link the cytoskeleton and the cell membrane (for a review, see, Bretscher et al., 2000). Together with ezrin and moesin, schwannomin and the transmembrane receptor CD44 form a molecular switch that specifies cell growth arrest or proliferation (Morrison et al., 2001).The role of loss of Nf2 function in development and tumorigenesis has been studied in various knockout mouse models. Embryos homozygous for Nf2 mutations causing either indirect skipping of exon 3 or 2-3 or direct deletion of exon 2 are lethal (McClatchey et al., 1998;Giovannini et al., 2000). They fail to initiate gastrulation between embryonic days 6.5 and 7.0 (McClatchey et al., 1997). Heterozygous Nf2 mutant mice do not mimic human NF2 but develop later in life (10-30 months) mainly osteomas and osteosarcomas showing loss of heterozygosity (LOH) for Nf2 (McClatchey et al., 1998;Giovannini et al., 2000). In addition, indications for a role of Nf2 loss in metastatic potential have been found (McClatchey et al., 1998). Previously, we have mimicked NF2 in conditonal Nf2 mutant mice with P0 promoter-directed Cre recombinase activity in Schwann cells (Giovannini et al., 2000). P0Cre;Nf2 fl...

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“…2). Immortalization with neu has been reported (Frederiksen et al, 1988;Sherman et al, 1999), but rare.…”

Section: Immortalizing Genesmentioning

confidence: 99%

Neural Stem/Progenitor Cell Clones as Models for Neural Development and Transplantation

Li¹,

Zhao²,

Shu³

et al. 2012

Neural Stem Cells and Therapy

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Overexpression of activated neu/erbB2 initiates immortalization and malignant transformation of immature Schwann cells in vitro

Cited by 16 publications

References 49 publications

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

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

Synergy of Nf2 and p53 mutations in development of malignant tumours of neural crest origin

Neural Stem/Progenitor Cell Clones as Models for Neural Development and Transplantation

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