TISSUE-SPECIFIC TUMORIGENESIS BY THE C-ERBB ONCOGENE

C-ERBB 癌基因引起的组织特异性肿瘤发生

• 批准号: 2084184
• 负责人: MICHAEL J MCMANUS
• 金额: $ 6.67万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-01 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2084184
• 关键词: biological signal transduction; carcinogenesis; chickens; complementary DNA; egg /ovum; enzyme substrate; growth factor receptors; human tissue; immunoaffinity chromatography; laboratory mouse; laboratory rabbit; mesenchyme; molecular oncology; monoclonal antibody; mutant; nucleic acid sequence; oncogenes; pediatric neoplasm /cancer; phosphorylation; protein tyrosine kinase; tissue /cell culture; tyrosine; vascular endothelium; western blottings

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.

生长因子的细胞表面受体在控制 细胞分裂，不同的肿瘤发生 禽类c-erbB基因编码一种 与人表皮生长同源的细胞表面受体 因子受体;两种基因产物均具有内在酪氨酸激酶 活动 已知突变型c-erbB编码受体介导 在禽类组织中转化以产生血管瘤、纤维肉瘤和 红细胞白血病 该项目的主要目标是确定 介导c-erbB 1肿瘤发生的细胞底物。 分析 细胞内底物通过其酪氨酸磷酸化， 与c-erbB受体的激酶结构域的相互作用将是 使用抗磷酸酪氨酸抗体结合 免疫印迹和免疫亲和层析技术。的 组织特异性c-erbB转化突变体，可用于这些 实验成功创造了一种强大而具体的识别方法， 在介导c-erbB致癌活性中重要的磷酸酪氨酸蛋白 在内皮、间充质和造血靶组织中。 此外，本发明还提供了一种方法， 抗磷酸酪氨酸蛋白单克隆抗体的制备 将允许免疫亲和纯化和进一步表征 这些基板。 在本研究计划的第一阶段，我们建议 产生抗磷酸酪氨酸抗体以检测磷酸化蛋白质 并鉴定c-erbB编码的酪氨酸激酶的底物。 期间 第二阶段，我们将继续研究c-erbB在肿瘤细胞中的信号转导。 鸟类系统（Erbb最初被发现），并将开始 检查人类儿科肿瘤。 许多小儿肿瘤是胚胎性的， 自然 由于蛋白酪氨酸激酶在胚胎发育中起着关键作用， 细胞生长和分化，胚胎激酶及其磷酸化 底物将进行研究，以阐明酪氨酸的潜在作用 激酶在儿科肿瘤发展中的作用 生成的试剂 这些研究过程（单克隆抗体、cDNA探针）可 最终可用作人类的诊断和/或预后指标 癌的