MEMBRANE SIGNAL TRANSDUCTION IN TUMOR PROMOTION

这些研究的目的是确定所需的生化事件 发生在肿瘤启动子-受体相互作用和激活之间 肿瘤转化的效应子。 候选第二信使 包括蛋白质磷酸化、活性氧产生和钙 动员。 来自抑制剂研究的证据表明， 自由基超氧阴离子是一种重要的早期介质， 促进肿瘤的佛波醇酯在JB 6小鼠表皮中的转化 细胞 超氧化物歧化酶活性显著降低， 12-O-十四酰基佛波醇-13-乙酸酯（TPA）治疗促敏 （P+），而不是促进抗性（P-）细胞，这表明因果关系 酶活性下降与超氧阴离子升高的关系， 以及这些事件与肿瘤促进的因果关系 转型 细胞外钙离子作为一种必需的信号转导器 用于促进JB 6细胞中的转化。 细胞外钙 TPA促进的转化所需的蛋白质似乎通过血浆进入细胞 膜通道 与阳离子结合蛋白结合的阳离子可以是 促进转化的重要信号转导事件。 的 三价阳离子镧替代钙激活蛋白 激酶C，但与钙不同，它（1）促进JB 6细胞的转化 在TPA的情况下，和（2）在某些情况下产生构象变化， 蛋白激酶C底物。 在未来，该项目将扩大 活性氧、钙和蛋白激酶信号转导研究， 与促进敏感性（pro）基因项目汇合， 研究基因表达。 镧结合的鉴定 将寻求促进相关蛋白质。 肿瘤启动子诱导型 蛋白质和磷蛋白将进行研究，以确定 识别原基因中信号序列的蛋白质。

The goal of these studies is to determine the required biochemical events that occur between tumor promoter-receptor interaction and the activation of effectors of neoplastic transformation. Candidate second messengers include protein phosphorylation, reactive oxygen generation, and calcium mobilization. Evidence from inhibitor studies indicates that the free radical superoxide anion is an essential early mediator of neoplastic transformation by tumor-promoting phorbol esters in JB6 mouse epidermal cells. Superoxide dismutase activity is substantially decreased by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment of promotion sensitive (P+) but not promotion resistant (P-) cells, suggesting a causal relationship between the enzyme decrease and elevation of superoxide anion, as well as a causal relationship of these events to promotion of neoplastic transformation. Extracellular calcium acts as a required signal transducer for promotion of transformation in JB6 cells. The extracellular calcium required for TPA-promoted transformation appears to enter cells via plasma membrane channels. Cation binding to cation binding proteins may be essential signal transduction events in promotion of transformation. The trivalent cation lanthanum substitutes for calcium in activating protein kinase C, but unlike calcium, it (1) promotes transformation of JB6 cells in the absence of TPA and (2) produces conformational changes in certain protein kinase C substrates. In the future this project will extend the reactive oxygen, calcium and protein kinase signal transduction studies and converge with the promotion sensitivity (pro) gene project in order to study gene expression. Identification of lanthanum-binding promotion-relevant proteins will be pursued. Tumor promoter inducible proteins and phosphoproteins will be studied in order to identify the proteins that recognize signal sequences in pro genes.