MEMBRANE SIGNAL TRANSDUCTION IN TUMOR PROMOTION

这些研究的目标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 肿瘤转化的效应因子。候选人第二信使 包括蛋白质磷酸化、活性氧生成和钙 动员。来自抑制剂研究的证据表明，游离的 自由基超氧阴离子是肿瘤早期必不可少的介质 促癌佛波醇酯在JB6小鼠表皮中的转化 细胞。超氧化物歧化酶活性因以下原因而显著降低 12-O-十四酰佛波醇-13-乙酸酯(TPA)对促进剂敏感性的治疗 (P+)而不是促进抵抗(P-)细胞，暗示原因 酶活性降低与超氧阴离子含量升高的关系 以及这些事件与促进肿瘤的因果关系 转型。细胞外钙是一种必需的信号转导因子 用于促进JB6细胞的转化。细胞外钙离子 TPA促进的转化所需的似乎通过血浆进入细胞 膜通道。阳离子结合蛋白的阳离子结合可能是 促进转化的关键信号转导事件。这个 三价阳离子镧在激活蛋白质中替代钙 激酶C，但与钙不同，它(1)促进JB6细胞转化 在没有TPA和(2)的情况下，在某些情况下会产生构象变化 蛋白激酶C底物。在未来，该项目将扩展 活性氧、钙和蛋白激酶信号转导研究 与促进敏感度(PRO)基因项目融合，以 研究基因表达。镧结合体的鉴定 将继续研究与促进相关的蛋白质。肿瘤促进剂可诱导 将对蛋白质和磷蛋白进行研究，以确定 识别前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.