Activated neu oncogene sequences in primary tumors of the peripheral nervous system induced in rats by transplacental exposure to ethylnitrosourea.

Perantoni, Alan O.; Rice, Jerry M.; Reed, Casie; Watatani, Masahiro; Wenk, Martin L.

doi:10.1073/pnas.84.17.6317

Cited by 92 publications

(53 citation statements)

References 40 publications

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“…The presence of c-erbB-2 abnormalities in salivary, gastric, renal, pulmonary and colonic adenocarcinoma (see Gullick & Ventner, 1989;Tal et al, 1988) and in experimental neural tumours (Lantos et al, 1986;Perantoni et al, 1987) …”

Section: Western Blottingmentioning

confidence: 99%

Pattern of expression of c-erbB-2 oncoprotein in human fetuses

Quirke

Pickles²,

Tuzi³

et al. 1989

Br J Cancer

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S_ry 1The pattern of expression of the c-erbB-2 oncoprotein was investigatdd in whole mount preparations of 11 human fetuses by immunocytochemistry using two polyclonal antibodies, 20N and 21N. c-erbB-2 was widely expressed within all three germ layers. Expression remained relatively constant in epitheliaL mesodermal and extraembryonic tissues, but varied over time during the development of the fetal skeleton. Western blotting failed to detect c-erbB-2 in normal fetal tissues but did confirm expression in a microvillous membrane preparation of placenta. c-erbB-2 expression is widespread in the human fetus and occurs at an earlier stage than epidermal growth factor receptor.The c-erbB-2 proto-oncogene encodes a 4.6 kb mRNA which specifies a 190,000 molecular weight glycoprotein with tyrosine kinase activity. This 1,255 amino acid protein reveals extensive sequence homology with the epidermal growth factor receptor (EGF-R), but unlike EGF-R, no ligand has yet been identified (for a review see Gullick & Venter, 1989). Amplification of the c-erbB-2 proto-oncogene has been demonstrated in a wide range of adenocarcinomas including those of the breast (Slamon et al., 1987;Venter et al., 1987;Van de Vijver et al., 1987, 1988, stomach (Yokota et al., 1986(Yokota et al., , 1988, salivary gland (Semba et al., 1985), kidney (Yokota et al., 1986) and lung (Cline & Battifora, 1987) and appears to be related to prognosis in breast cancer (Slamon et al., 1987;Zhou et al., 1987). The presence of amplification in colonic adenocarcinoma has been reported (Tal et al., 1988), but it is unclear if this is a frequent event as it has not been detected by other workers (Yokota et al., 1986).The physiological action of the c-erbB-2 receptor protein is unknown and its distribution in human fetal and normal tissue has yet to be fully characterised. c-erbB-2 mRNA was widely expressed in organ digests from a single human fetus (Coussens et al., 1985) but its site within these tissues has not been identified. Expression of the neu oncogene, the rat equivalent of c-erbB-2, with which it has 88% homology, has been described in fetal rats (Kokai et al., 1987) al., 1985, 1986 Bernards et al., 1987) or anti-oncogene therapy.We have investigated the presence and distribution of the c-erbB-2 protein by immunocytochemistry and Western blotting in a series of human fetuses and placentae using two previously described polyclonal antibodies . Materials and methodsFifteen whole human fetuses from spontaneous abortions were collected over several years and stored in 10% formalin. After processing and embedding four were discarded owing to the presence of mild to severe autolysis, leaving 11 well preserved fetuses for study. Estimated gestational ages were determined by a combination of foot length, crown rump length and histological assessment of tissue maturity and ranged from 6 to 12 weeks. Fetuses larger than 12 weeks could not be sectioned whole and were therefore not included in this study. Tissue from first trimester, second trimester and term p...

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Section: Western Blottingmentioning

confidence: 99%

Pattern of expression of c-erbB-2 oncoprotein in human fetuses

Quirke

Pickles²,

Tuzi³

et al. 1989

Br J Cancer

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“…The histologic diagnosis is supported by features including wavy to plump spindle cells formed whorls, loose myxoid (Antoni B), and more cellular (Antoni A) areas, nuclear palisades, rare Verocay bodies, focal large dark atypical spindle-shaped nuclei, infiltrative border, and mitoses (two per ten 400x fields; not shown) (Enzinger and Weiss, 1995;Hruban et al, 1990). Peripheral nerve sheath tumors have also been induced by ENU in the rat (Kindler-Rohrborn et al, 1999;Koestner et al, 1971;Nikitin et al, 1991;Perantoni et al, 1987). Two cavernous hemangiomas were also found in the mutagenized zebrafish.…”

Section: Beckwith Et Almentioning

confidence: 99%

Ethylnitrosourea Induces Neoplasia in Zebrafish (Danio rerio)

Beckwith

Moore

Tsao-Wu

et al. 2000

Laboratory Investigation

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SUMMARY:The zebrafish (Danio rerio) has been successfully used to discover hundreds of genes involved in development and organogenesis. To address the potential of zebrafish as a cancer model, it is important to determine the susceptibility of zebrafish to tumors. Germ line mutations are most commonly induced for zebrafish mutant screens by exposing adult male zebrafish to the alkylating agent, ethylnitrosourea (ENU). To determine whether ENU induces tumors, we compared the incidence of tumors in ENU-treated fish with untreated controls. Interestingly, 18 of 18 (100%) fish mutagenized with either 2.5 or 3.0 mM ENU developed epidermal papillomas, which numbered 1 to 22 per fish, within 1 year of treatment. The induced epidermal lesions included epidermal hyperplasia, flat papillomas (0.2 to 1.2 mm), and pedunculated papillomas (1.2 to 8 mm in greatest dimension), but no skin cancers. Angiogenesis was evident in papillomas larger than approximately 1 mm. All but two papillomas contained the three cell types (keratinocytes, club, and mucous cells) of normal zebrafish epidermis; histologic variants lacked either club cells or mucous cells. Two cavernous hemangiomas and a single malignant peripheral nerve sheath tumor were also found in the treated fish. None of five untreated controls developed tumors. These studies establish the feasibility of the zebrafish as an experimental model for the study of skin tumors. (Lab Invest 2000, 80:379-385).

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“…Comparisons of the activated and normal versions of the neu gene have demonstrated that neu gene activation in the cell lines derived from intracranial tumors and in primary schwannomas invariably involves a T:A --> A:T transversion mutation in codon 664 (15,38). Unexpectedly, this alteration, which changes valine to glutamic acid, falls within the putative transmembrane domain.…”

Section: The Met Genementioning

confidence: 99%

“…However, the identification of these tumors was equivocal because no histological examination of the primary tumors' tissue was reported and because schwannomas may also develop intracranially. Indeed, an extensive study of oncogene activation in primary glial tumors and schwannomas that developed in transplacentally exposed F344 rats revealed that neu activation occurred exclusively in schwannomas; of 59 gliomas examined, none showed neu gene activation (38).…”

Section: The Met Genementioning

confidence: 99%

The role of non-ras transforming genes in chemical carcinogenesis.

Cooper

1991

Environ Health Perspect

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DNA transfection experiments using the NIH 3T3 mouse fibroblast cell line have demonstrated that chemically induced tumors and chemically transformed cell lines frequently contain dominant transforming genes. Although many of the genes detected using the NIH 3T3 transfection-transformation assay are activated versions of H-ras, K-ras, and N-ras, in some experimental systems activated forms of genes such as met and neu that are unrelated to ras have been observed. The activated met gene was originally detected in a human cell line that had been transformed by exposure to N-methyl-N'-nitro-N-nitrosoguanidine. Subsequent studies demonstrated that the met proto-oncogene encodes a novel growth factor receptor and that gene activation involves the production of a chimeric gene in which the regions of met encoding the extracellular and transmembrane domains of the receptor are replaced by the 5'-region of an unrelated gene called trp. The activated neu gene was detected in tumors of the nervous system that arose in mice following transplacental exposure to N-ethyl-N-nitrosourea. The neu gene also encodes a novel growth factor receptor but, in contrast to met, its activation involves a single T:A----A:T point mutation in the region of the neu gene encoding the receptor transmembrane domain. The presence of genetic alterations in chemically induced malignancies has also been assessed in cytogenetic studies and by Southern analysis of DNA from neoplastic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

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Activated neu oncogene sequences in primary tumors of the peripheral nervous system induced in rats by transplacental exposure to ethylnitrosourea.

Cited by 92 publications

References 40 publications

Pattern of expression of c-erbB-2 oncoprotein in human fetuses

Pattern of expression of c-erbB-2 oncoprotein in human fetuses

Ethylnitrosourea Induces Neoplasia in Zebrafish (Danio rerio)

The role of non-ras transforming genes in chemical carcinogenesis.

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