Oncogenic activation of the neu-encoded receptor protein by point mutation and deletion.

Abstract

The rat neu gene, which encodes a receptor‐like protein homologous to the epidermal growth factor receptor, is frequently activated by a point mutation altering a valine residue to a glutamic acid residue in its predicted transmembrane domain. Additional point mutations have been constructed in a normal neu cDNA at and around amino acid position 664, the site of the naturally arising mutation. A mutation which causes a substitution of a glutamine residue for the normal valine at residue 664 leads to full oncogenic activation of the neu gene, but five other substitutions do not. Substituted glutamic acid residues at amino acid positions 663 or 665 do not activate the neu gene. Thus only a few specific residues at amino acid residue 664 can activate the oncogenic potential of the neu gene. Deletion of sequences of the transforming neu gene demonstrates that no more than 420 amino acids of the 1260 encoded by the gene are required for full transforming function. Mutagenesis of the transforming clone demonstrates a correlation between transforming activity and tyrosine kinase activity. These data indicate that the activating point mutation induces transformation through (or together with) the activities of the tyrosine kinase.

Overexpression of C-NEU and C-MET during rat liver cholangiocarcinogenesis: A link between biliary intestinal metaplasia and mucin-producing cholangiocarcinoma

“…25,30,35 Our findings suggest that the increased levels of expression of c-neu and c-met in the ChCs is, at least in the case of an early-and late-passaged transplantable tumor, not the result of gene amplification, and in the case of c-neu is not likely the result of an oncogenic point mutation at nucleotide 2021 in the transmembrane domain of this proto-oncogene when expressed in a late-passaged tumor. Overexpression of c-erbB-2 in the apparent absence gene amplification 36,37 or mutational activation 38 has also been observed in human pancreatic cancer.…”

Neuroendocrine Lung Tumors: Grade Correlates with Proliferation but not Angiogenesis

“…These studies parallel the discovery of dominant oncogenes, whose transforming ability was discovered by their ability to convert preneoplastic cells with deletions in tumor suppressor genes into fully malignant and angiogenic neoplasms (23)(24)(25)(26). The loss of a nuclear tumor suppressor gene is an early event in the elaborate sequence that leads to tumorigenesis.…”

DNA vaccination with full-length or truncated Neu induces protective immunity against the development of spontaneous mammary tumors in HER-2/neu transgenic mice

“…1,2 Amplification and mutation 3,4 of HER-2/neu gene plays a pathogenic role in several malignancies. A significant proportion of human cancers including carcinoma of the breast, ovary, uterus, stomach and adenocarcinoma of the lung display HER-2/neu amplification.…”