BASIS FOR TRANSFORMATION BY FUJINAMI SARCOMA VIRUS

富士肉瘤病毒转化的基础

• 批准号: 3458702
• 负责人: DAVID A FOSTER
• 金额: $ 11.66万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-25 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3458702
• 关键词: Aves; Retroviridae; Retroviridae disease; biological signal transduction; enzyme inhibitors; gene expression; genetic transcription; laboratory rat; neoplasm /cancer pharmacology; oncogenes; phospholipase A2; phospholipase C; protein kinase C; protein tyrosine kinase; temperature sensitive mutant; viral carcinogenesis; virus genetics

The objective of the proposed research is to understand how protein- tyrosine kinase oncongenes transform cells. The major emphasis is on the fps gene of Fujinami sarcoma virus. We will characterize signal transduction pathways used by v-fps to transform cells. We have developed a pharmaco-genetic approach for identifying signal transduction intermediates used by the v-fps gene product to transduce signals to the nucleus. Elevating the protein-tyrosine kinase activity of a temperature-sensitive derivative of v-fps, leads to the rapid transcriptional activation of the recently characterized 9E3 gene whose expression correlates with transformation (Sugano et al., Cell 49, 1321,-328, 1987). Drugs that interfere with known signal transduction intermediates are used to block the induction of 9E3 gene expression. In this way, we can determine if specific signal transduction intermediates are required for v-fps to induce expression of the transformation-related 9E3 gene. The pharmacological approach involves the generation of detailed drug- sensitivity profiles (DSPs) for inhibitors of signal transduction that are diagnostic for the involvement of specific signal transduction intermediates. Using several protein kinase C requirement. In addition, we have preliminary data suggesting a requirement for protein kinase C, a cholera toxin-sensitive G-protein, phospholipase C, and phospholipase A2 in the v-fps induction of 9E3 gene expression. Experiments proposed here will directly demonstrate the involvement of these implicated signal transduction intermediates in transformation by v-fps. The data to be generated from these studies may provide new targets and strategies for cancer chemotherapy in cases where protein-tyrosine kinase activity has been implicated.

拟议研究的目的是了解蛋白质如何 酪氨酸激酶肿瘤转化细胞。主要重点是 Fujinami肉瘤病毒的FPS基因。我们将表征信号 V-FPS用于转化细胞的转导途径。我们已经开发了 用于识别信号转导中间体的药物遗传学方法 由V-FPS基因产物用于将信号传递到核。 抬高温度敏感的蛋白质酪氨酸激酶活性 V-FPS的导数导致快速转录激活 最近表征了9e3基因的表达与 转化（Sugano等人，Cell 49，1321，-328，1987）。吸毒 干扰已知信号转导中间体用于阻止 9E3基因表达的诱导。这样，我们可以确定是否 V-FPS需要特定的信号转导中间体才能诱导 与转化相关的9E3基因的表达。 药理方法涉及生成详细的药物 - 对信号转导抑制剂的灵敏度曲线（DSP）为 诊断特定信号转导的参与 中间人。使用几种蛋白激酶C的需求。另外，我们 有初步数据表明对蛋白激酶C的要求，A 霍乱毒素敏感的G蛋白，磷脂酶C和磷脂酶A2中的A2 9E3基因表达的V-FPS诱导。这里提出的实验将 直接证明这些涉及信号的参与 通过V-FPS转化的转导中间。数据是 这些研究产生的可能为新的目标和策略提供 在蛋白 - 酪氨酸激酶活性的情况下，癌症化学疗法 被暗示。