TISSUE-SPECIFIC TUMORIGENESIS BY THE C-ERBB ONCOGENE

细胞表面生长因子受体在调控细胞生长中起着重要作用 细胞分裂，不同的肿瘤发生。禽类c-erb基因编码一个 与人类表皮生长同源的细胞表面受体 因子受体；两种基因产物都具有固有的酪氨酸激酶 活动。已知突变的c-erbB编码的受体介导 禽类组织发生转化，产生血管瘤、纤维肉瘤和 红细胞性白血病。该项目的主要目标是确定 介导c-erbB-1癌发生的细胞底物。分析了几个问题 细胞内底物通过它们的酪氨酸磷酸化 与c-erbB受体的激活域的相互作用将是 结合使用抗磷酸酪氨酸抗体和 免疫印迹和免疫亲和层析技术。这个 组织特异性c-erbB转化突变体可用于这些 实验创造了一种强大而具体的识别方法 磷酸化酪氨酸蛋白在介导c-erbB致癌活性中的作用 在内皮、间充质和造血靶组织中。此外, 抗磷酸酪氨酸蛋白单抗的制备 将允许免疫亲和纯化和进一步鉴定 这些底物。在本研究计划的第一阶段，我们建议 产生抗磷酸化酪氨酸抗体以检测磷酸化蛋白 并鉴定c-erbB编码的酪氨酸激酶的底物。在.期间 第二阶段，我们会继续研究c-erbb在 鸟类系统(最初在其中发现ErbB)，并将开始 检查人类儿科肿瘤。许多儿科肿瘤是胚胎性的 大自然。由于蛋白酪氨酸激酶在胚胎发育过程中起着关键作用 细胞生长和分化、胚胎蛋白激酶及其磷酸化 将研究底物以阐明酪氨酸的潜在作用。 蛋白激酶在儿童肿瘤发生发展中的作用。中产生的试剂 这些研究的过程(单抗、cDNA探针)可能 最终作为人类诊断和/或预后指标是有用的 癌症。

Cell surface receptors for growth factors play a major role in controlling cell division, different tumorigenesis. The avian c-erbB gene encodes a cell surface receptor that is homologous to the human epidermal growth factor receptor; both gene products possess intrinsic tyrosine kinase activity. It is known that mutant c-erbB encoded receptors mediate transformation in avian tissues to produce hemangiomas, fibrosarcomas and eyrthroleukemias. The primary goal of this project is to identify the cellular substrates which mediate c-erbB 1 oncogenesis. The analysis of intracellular substrates which become tyrosine phosphorylated through their interaction with the kinase domain of the c-erbB receptor will be accomplished using antiphosphotyrosine antibodies in conjunction with immunoblotting and immunoaffinity chromatographic techniques. The tissue-specific c-erbB transforming mutants that are available for these experiments win create a powerful and specific method of identifying phosphotyrosine proteins important in mediating c-erbB's oncogenic activity in endothelial, mesenchymal and hematopoietic target tissues. In addition, the production of monoclonal antibodies against phosphotyrosine proteins will allow immunoaffinity purification and further characterization of these substrates. During Phase I of this research plan we propose to generate antiphosphotyrosine antibodies to detect phosphorylated proteins and to identify substrates of the c-erbB encoded tyrosine kinase. During Phase II, we will continue to study signal transduction by c-erbB in the avian system (in which erbb was originally discovered) and will begin to examine human pediatric tumors. Many pediatric tumors are embryonal in nature. Since protein tyrosine kinase play a critical role in embryonal cell growth and differentiation, embryonal kinases and their phosphorylated substrates will be investigated to elucidate the potential role of tyrosine kinases in the development of pediatric tumors. The reagents generated in thc course of these studies (monoclonal antibodies, cDNA probes) may ultimately be useful as diagnostic and/or prognostic indicators in human cancers.