MEMBRANE SIGNAL TRANSDUCTION IN TUMOR PROMOTION

这些研究的目标是确定所需的生化事件 发生在肿瘤促进剂或生长因子-受体相互作用之间 以及肿瘤转化效应因子的激活。侯选人 第二信使包括依赖于蛋白质的蛋白质磷酸化 激酶C(PKC)或表皮生长因子(EGF)受体激酶和 激酶调节的基因表达的反式激活。佛波酯 敏感和耐药的JB6细胞在PKC亚型上没有差异 这表明，差分敏感性的基础是 在受体的远端。12-0-十四酰-佛波醇-13-的研究进展 醋酸酯(TPA)诱导的基因主要集中在受 转录因子AP-1(Jun/Fos复合体)。肿瘤 TPA和EGF启动子诱导P+细胞AP-1调节的基因表达 P-JB6细胞。这表明AP-1调节的基因表达可能是 肿瘤促进剂诱导转化所必需的。它的作用机制 TPA的差异反式激活和转化似乎涉及 C-jun的基础和诱导水平不同，但 不涉及c-fos、fos B、jun D或jun B.的差异诱导 新的Fra-1相关蛋白在P-细胞中被诱导，但在P+细胞中不被诱导。这些 观察表明，c-jun增强了Fra-1相关蛋白 抑制AP-1的激活和对肿瘤的转化反应 推动者。此外，c-jun和Fra-1的磷酸化是 在P-和P+细胞中的差异调节，提示第二个 与推广相关的监管模式。用基因敲除技术观察最新情况 显性负性过表达对c-jun依赖的AP-1活性的影响 C-jun突变，提示AP-1在肿瘤启动子诱导中是必需的 转换；即，对于P+反应。C-jun和AP-1的过表达， 虽然不足以进行P-to P+级进，但对于 P+到肿瘤细胞(TX)进展。

The goal of these studies is to determine the required biochemical events that occur between tumor promoter or growth factor-receptor interaction and the activation of effectors of neoplastic transformation. Candidate second messengers include protein phosphorylation dependent on protein kinase C (PKC) or epidermal growth factor (EGF) receptor kinase and kinase-regulated trans-activation of gene expression. Phorbol ester sensitive and resistant JB6 cells show no differences in PKC isotypes expressed, suggesting that the basis for differential sensitivity is distal to the receptor. Recent studies on 12-0-tetradecanoyl-phorbol-13- acetate (TPA)-inducible genes have focused on those regulated by the transacting transcriptional factor AP-1 (Jun/Fos complex). The tumor promoters TPA and EGF induce AP-1-regulated gene expression in P+ but not P- JB6 cells. This suggests that AP-1-regulated gene expression may be required for tumor promoter-induced transformation. The mechanism of differential trans-activation and transformation by TPA appears to involve differential basal and induced levels of c-Jun mRNA and protein but does not involve differential induction of c-fos, fos B, jun D, or jun B. A novel Fra-1 related protein is induced in P- but not in P+ cells. These observations suggest that c-Jun enhances and the Fra-1 related protein inhibits AP-1 activation and the transformation response to tumor promoters. In addition, the phosphorylation of c-Jun and Fra-1 is differentially regulated in P- and P+ cells, suggesting a second promotion-relevant mode of regulation. Recent observation with knockout of c-jun-dependent AP-1 activity by overexpression of a dominant negative c-jun mutant, suggests that AP-1 is required for tumor promoter-induced transformation; i.e., for P+ response. Overexpression of c-jun and AP-1, while not sufficient for P- to P+ progression, is, however, sufficient for P+ to tumor cell (Tx) progression.