BASIS FOR TRANSFORMATION BY FUJINAMI SARCOMA VIRUS

这项拟议的研究的目的是了解蛋白质是如何- 酪氨酸激酶癌基因转化细胞。主要的重点是 Fujinami肉瘤病毒的FPS基因。我们将描述Signal V-fps用于转化细胞的转导通路。我们已经开发出一种 鉴定信号转导中间产物的药物遗传学方法 V-fps基因产物用来将信号传递到细胞核。 提高温度敏感型菌株的蛋白酪氨酸激酶活性 V-fps的衍生物，导致快速转录激活 最近鉴定的9E3基因，其表达与 转化(Sugano等人，细胞49,1321，-328,1987)。毒品，即 干扰已知信号转导的中间产物被用来阻断 9E3基因的诱导表达。这样，我们就可以确定是否 V-fps的诱导需要特定的信号转导中间产物。 转化相关基因9E3的表达。 药理学方法包括产生详细的药物- 信号转导抑制剂的敏感性曲线(DSP) 特异性信号转导参与的诊断 中间体。使用几种蛋白激酶C的要求。此外，我们 有初步数据表明需要蛋白激酶C，a 霍乱毒素敏感的G蛋白、磷脂酶C和磷脂酶A2 V-fps对9E3基因表达的诱导。这里提出的实验将 直接证明了这些隐含信号的参与 V-fps转化过程中的转导中间体。数据将被 从这些研究中产生的数据可以提供新的目标和战略 蛋白酪氨酸激酶活性为 被牵连了。

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.