BIOLOGICAL AND BIOCHEMICAL ASPECTS OF RAS SIGNALLING

原癌基因在调节细胞生长方面起着关键作用， 但很难将这些分子的结构与 它们在细胞内的生物学功能..这项提案的目标是 是为了确定几个关键的原癌基因在 控制细胞分裂。在过去的工作中，一种中和抗体 鉴定了原癌基因ras，并显微注射到活细胞中。 这种治疗对人卵巢癌细胞增殖能力的影响 然后细胞表明ras蛋白在正常增殖中的功能。 很明显，细胞内的ras蛋白不仅对 但ras活性对细胞的功能至关重要 一些但不是所有的逆转录病毒癌基因。根据这些结果，我们 已经提出ras蛋白可能起到传递 从一类原癌基因到另一类原癌基因的增殖信号，以及 磷脂代谢参与了这一信号传递。 这项提议的目的是检验这些关键假设。 首先，针对其他原癌基因的中和抗体被认为是 在假定的信号转导的不同阶段的功能 将产生并测试路径。这些抗体将允许 多种原癌基因功能假说的直接检验 在一条信号转导途径中共同作用。此外，此前的研究表明， 抗ras抗体提示磷脂代谢可能 参与调节ras蛋白的生物活性。 最近的研究提供了直接的生化证据，证明这可能 情况就是这样。如果这些结果能够得到验证和扩展，可能会 提供了细胞内ras蛋白活性的第一个指标 可能在有丝分裂过程中受到控制。第二个目标是 因此，拟议的研究是为了验证和扩展这些初步研究。 这项工作的重要性强调了一个事实，尽管细胞 RAS蛋白被认为在控制黄斑狼疮的过程中起着核心作用。 扩散，目前还没有报道其他迹象可以解释这种 这些蛋白质的生物活性。最后，这些微量注射 生化研究将放在生物学的背景下进行。这个 癌基因的作用将被置于与已知的时间关系中 细胞分裂的生物标志。 这些研究构成了一种独特的生物分析方法 增殖基因。所获得的信息无疑将有助于 直接在分子上理解肿瘤的形成，因为这些 基因是自然人类肿瘤中最常发生突变的基因之一。 此外，要检测的生物标志物包括 抗肿瘤治疗中常用的抗增殖剂。

Proto-oncogenes play a critical role in the regulation of cell growth, but it has been difficult to relate the structure of these molecules to their biological functions within the cell.. The goal of this proposal is to determine the role of several critical proto-oncogenes in the control of cell division. In past work a neutralizing antibody to the proto-oncogene ras was identified and microinjected into living cells. The consequences of this treatment upon the proliferative capacity of the cell then indicated the function of ras proteins in normal proliferation. It was clear not only that cellular ras proteins were critical for proliferation, but that ras activity was essential to the function of some but not all retroviral oncogenes. On the basis of these results we have suggested that ras proteins might function to transmit a proliferative signal from one class of proto-oncogenes to another, and that phospholipid metabolism is involved in this signalling. The objective of this proposal is to test these critical hypotheses. First, neutralizing antibodies to other proto-oncogenes believed to function at different stages of the postulated signal transduction pathway will be produced and tested. These antibodies will allow a direct test of the hypothesis that various proto-oncogenes function together in a signal transduction pathway. In addition, previous studies with the anti-ras antibody suggested that phospholipid metabolism might be involved in regulating the biological activity of ras proteins. Recent studies have provided direct biochemical evidence that this might be the case. If these results can be verified and expanded it might provide the first indication of how the activity of cellular ras proteins might be controlled during mitogenesis. The second objective of the proposed study is, therefore, to verify and expand these initial studies. The importance of this work is emphasized by the fact that while cellular ras proteins are believed to play a central role in the control of proliferation, no other indication has yet been reported to explain the biological activation of these proteins. Finally, these microinjection and biochemical studies will be placed in a biological context. The action of oncogenes will be placed in temporal relationship to the known biological marker of cell division . These studies constitute a unique approach in the biological analysis of proliferative genes. the information obtained will undoubtedly aid directly in a molecular understanding of tumor formation since these genes are among those most often mutated in natural human tumors. Furthermore, the biological markers to be tested included antiproliferative agents commonly utilized in anti-tumor therapy.