THE ROLE OF PROTO-ONCOGENES ENCODING GROWTH FACTOR RECEPTORS IN NEOPLASIA

第二个成员，erbB原癌基因家族中的erbB-2，有 在一例乳腺癌中通过基因扩增进行鉴定 与表皮生长因子(EGF)有密切的结构同源性 受体基因。随后，在存在或存在时过度表达 基因扩增缺失已被确定为发病机制 激活人乳腺肿瘤细胞株中的erbB-2。这些 观察结果与在体外的发现是平行的 人erbB-2编码序列在蛋白质中的高效表达 与人类乳腺肿瘤细胞中观察到的水平相似的是 能够将转化的表型赋予NIH/3T3细胞。 乳腺癌组织中erbB-2和EGF受体蛋白水平分析 组织中有45%(24/53)的组织中有erbB-2和EGF的过度表达 9%(4/47)的患者进行了erbB-2受体分析。基因 ErbB-2和EGF受体扩增与高血压病 蛋白表达水平分别为19%和4% 患者进行了分析。增强受体基因的一致性 在原发灶和转移灶中的表达，结合 观察到在乳腺肿瘤中可以检测到这种变化 早在第一阶段和第二阶段，就表明原癌基因 激活导致生长因子过表达 受体分子可以在相对较早的阶段出现 人类乳腺肿瘤的发生发展。ErbB-3，一个新的成员 在正常基因组中发现了erbB原癌基因家族。 使用v-erbB作为探针的人DNA在降低严格程度下的应用 杂交条件。基因组外显子的特征 序列显示出与酪氨酸成员的结构同源性 蛋白水解酶家族。预测的这些基因组的氨基酸序列 外显子表明该区域与酪氨酸的同源性更高 EGF受体和erbB-2蛋白的激活域比任何 其他已知的酪氨酸激酶蛋白。Northern印迹分析使用 含有外显子的erbB-3探针鉴定出6.5kb的基因特异性 不同组织来源的正常细胞和肿瘤细胞中的mRNA。

A second member, erbB-2, in the erbB proto-oncogene family, had been identified based on gene amplification in a mammary carcinoma and close structural homology to the epidermal growth factor (EGF) receptor gene. Subsequently, overexpression in the presence or absence of gene amplification has been determined as the mechanism activating erbB-2 in human mammary tumor cell lines. These observations were paralleled by the finding that in vitro overexpression of the human erbB-2 coding sequence at protein levels similar to those observed in human mammary tumor cells was capable of conferring the transformed phenotype onto NIH/3T3 cells. Analysis of erbB-2 and EGF receptor protein levels in mammary tumor tissues revealed overexpression of erbB-2 in 45% (24/53) and EGF receptor of erbB-2 in 9% (4/47) of the patients analyzed. Gene amplification of erbB-2 and EGF receptor was associated with high protein expression levels in 19% and 4%, respectively, of the patients analyzed. Concordance of increased receptor gene expression in primary and metastatic lesions, combined with the observation that such alterations are detectable in mammary tumors as early as stages I and II, indicate that proto-oncogene activation resulting in the overexpression of growth factor receptor molecules can occur at a relatively early stage in the development of human mammary neoplasia. ErbB-3, a novel member of the erbB proto-oncogene family, was identified in normal genomic human DNA using v-erbB as a probe under reduced stringency hybridization conditions. Characterization of genomic exon sequences revealed structural homology to members of the tyrosine kinase family. The predicted amino acid sequence of these genomic exons indicated the closer homology of this region to the tyrosine kinase domains of the EGF receptor and erbB-2 protein than to any other known tyrosine kinase protein. Northern blot analysis using an exon-containing erbB-3 probe identified a 6.5kb gene-specific mRNA in normal and neoplastic cells of various tissue origin.