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.

这项研究的目的是了解蛋白质- 酪氨酸激酶癌基因转化细胞。主要重点是 Fujinami肉瘤病毒的fps基因。我们将描述信号 V-FPS用于转化细胞的转导途径。我们已经开发出一种 用于鉴定信号转导中间体的药物遗传学方法 由v-fps基因产物用来将信号传递到细胞核。 提高温度敏感性蛋白质酪氨酸激酶活性 v-fps的衍生物，导致快速的转录激活， 最近鉴定的9 E3基因，其表达与 转化（Sugano等人，Cell 49，1321，-328，1987）。的药物 干扰已知信号转导中间体用于阻断 诱导9 E3基因表达。这样，我们就可以确定， V-FPS需要特异性信号转导中间体来诱导 转化相关的9 E3基因的表达。 药理学方法涉及产生详细的药物- 敏感性曲线（DSP）的信号转导抑制剂， 特异性信号转导参与的诊断 中间体的使用几种蛋白激酶C的要求。另外我们 有初步数据表明需要蛋白激酶C， 霍乱毒素敏感G蛋白、磷脂酶C和磷脂酶A2 v-fps诱导9 E3基因表达。这里提出的实验将 直接证明了这些牵连信号的参与 V-FPS转化中的转导中间体。的数据 从这些研究中产生的可能提供新的目标和战略， 在蛋白酪氨酸激酶活性具有 被牵连。