Chan R, Muller W J, Siegel P M
Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada.
Ann N Y Acad Sci. 1999;889:45-51. doi: 10.1111/j.1749-6632.1999.tb08722.x.
Amplification and overexpression of erbB-2/neu is an important determinant in the initiation and progression of human breast cancer. Indeed, transgenic mice that over-express the neu proto-oncogene heritably develop mammary adenocarcinomas. Tumorigenesis in these transgenic strains is associated with activation of the intrinsic catalytic activity of Neu. In many of these tumors, activation of Neu occurs as a result of somatic mutations located within the transgene itself. Examination of the altered neu transcripts revealed the presence of in-frame deletions that encode aberrant Neu receptors lacking 5 to 12 amino acids within the extracellular domain proximal to the transmembrane region of Neu. In addition to these deletion mutants we have also detected single point mutations within this juxta-transmembrane region. The majority of the mutations analyzed affect the one of several conserved cysteine residues present within this region. Introduction of these activating mutations into the wild-type neu cDNA results in its oncogenic conversion. Taken together, these observations suggest that this cysteine-rich region plays an important role in regulating the catalytic activity of Neu.
erbB-2/neu的扩增和过表达是人类乳腺癌发生和进展的重要决定因素。实际上，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。这些转基因品系中的肿瘤发生与Neu内在催化活性的激活有关。在许多这些肿瘤中，Neu的激活是由于转基因自身内的体细胞突变所致。对改变后的neu转录本的检查揭示了框内缺失的存在，这些缺失编码在Neu跨膜区域近端的细胞外结构域内缺少5至12个氨基酸的异常Neu受体。除了这些缺失突变体，我们还在这个近跨膜区域检测到单点突变。分析的大多数突变影响该区域存在的几个保守半胱氨酸残基之一。将这些激活突变引入野生型neu cDNA会导致其致癌转化。综上所述，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。
