Muller W J, Ho J, Siegel P M
Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada.
Biochem Soc Symp. 1998;63:149-57.
Recent evidence has suggested that amplification and overexpression of erbB-2/neu is an important determinant in the initiation and progression of human breast cancer. Consistent with this assertion is the observation that transgenic mice that overexpress the neu proto-oncogene heritably develop mammary adenocarcinomas. More recently, we have demonstrated that activation of neu in many of these tumours occurs as a result of somatic mutations located within the transgene itself. Indeed, careful examination of the altered neu transcripts revealed the presence of in-frame deletions that encode aberrant Neu receptors lacking 5-12 amino acids within the extracellular domain, located adjacent to the transmembrane domain. Interestingly, the majority of the deletions analysed affect one of several conserved cysteine residues present within this region. Moreover, introduction of these activating mutations into the wild-type neu cDNA results in its oncogenic conversion. These observations suggest that this cysteine-rich region plays an important role in regulating the catalytic activity of Neu.
最近的证据表明，erbB-2/neu的扩增和过表达是人类乳腺癌发生和发展的一个重要决定因素。与此观点一致的是，观察到过表达neu原癌基因的转基因小鼠会遗传性地发生乳腺腺癌。最近，我们证明在许多这些肿瘤中，neu的激活是由于转基因自身发生体细胞突变所致。事实上，仔细检查改变后的neu转录本发现存在框内缺失，这些缺失编码的异常Neu受体在跨膜结构域附近的细胞外结构域内缺少5 - 12个氨基酸。有趣的是，分析的大多数缺失影响该区域内存在的几个保守半胱氨酸残基之一。此外，将这些激活突变引入野生型neu cDNA会导致其致癌转化。这些观察结果表明，这个富含半胱氨酸的区域在调节Neu的催化活性中起重要作用。
