CELL/CELL COMMUNICATION IN CARCINOGENESIS

描述：（申请人的摘要）本发明的长期目标是： 续期申请是审查的监管机制， GJIC及其在肿瘤发生中的作用工作假设 继续测试的是GJIC的下调，在 癌基因的转录、翻译或翻译后水平， 化学肿瘤促进剂，和特定的激素和生长 因子，允许启动的细胞逃避抑制作用， 包围和沟通细胞。根据（a）示范 许多化学肿瘤促进剂（即，例如，TPA，DDT，TCDD，糖精， 苯巴比妥等），生长因子（EGF，TGF-α），癌基因（src，ras， raf、neu、mos）下调GJIC;（B）约14个间隙连接 基因已被分离;（c）许多新的技术来衡量 已经开发了GJ的功能;（d）抗肿瘤促进化学物质 （类维生素A、类胡萝卜素、绿色茶成分等）已显示 上调GJIC;和（e）非交通性癌症的基因工程 细胞或具有特异性GJ基因或抗- 有义GJ基因分别改变这些细胞的生长调节， 此应用程序旨在检查三个具体目标，以建立在 申请人以前对该领域的贡献。第一个目标是 来研究特定的信号转导机制， 与化学、生长因子或致癌基因调节相关 GJIC和对细胞增殖的生物学效应， 分化第二个目标是研究 多种肿瘤抑制基因在GJIC的上调中的作用。第三 AIM将利用独特的体外细胞分化模型系统， 正常人乳腺上皮干细胞，研究 GJ在分化中的潜在作用 GJIC与肿瘤分化的关系。此逻辑树 应用是，GJIC在多细胞生物体中是必需的， 固体中细胞增殖和分化调控 组织中GJIC的可逆调节是由细胞外 通信信号，可以触发信号转导内 细胞调节GJ的转录，翻译或后 在正常细胞中的翻译水平。癌症，一种细胞疾病 增殖和分化，似乎已经被阻止， 在细胞外、细胞内和GJIC间的联系中， 通信拟议的研究旨在验证这一点 假说.

DESCRIPTION: (Applicant's Abstract) The long term objective of this renewal application is to examine the mechanism of the regulation of GJIC and its potential role in carcinogenesis. The working hypothesis which continues to be tested is that down-regulation of GJIC, at the transcriptional, translational or posttranslational levels by oncogenes, chemical tumor promoting agents, and specific hormones and growth factors, permits initiated cells to escape the suppressing effects of surrounding and communicating cells. Based on (a) the demonstration that many chemical tumor promoters (i. e., TPA, DDT, TCDD, saccharin, phenobarbital, etc.), growth factors (EGF, TGF- a), oncogenes (src, ras, raf, neu, mos) down-regulate GJIC; (b) approximately 14 gap junction genes have been isolated; (c) many new techniques to measure the function of GJ's have been developed; (d) anti-tumor promoting chemicals (retinoids, carotenoids, green tea components, etc.) have been shown to up-regulate GJIC; and (e) genetic engineering of non-communicating cancer cells or of normal communicating cells with specific GJ genes or anti- sense GJ gene, respectively, alters growth regulation in these cells, this application is designed to examine three specific aims to build on the applicant's previous contribution to this field. The first aim is to study the specific signal transducing mechanisms which might be associated with either chemical, growth factor or oncogene modulation of GJIC and the biological effects on cell proliferation or differentiation. The second aim is to study the potential role of various tumor suppressor genes in the up-regulation of GJIC. The third aim will utilize a unique in vitro cell differentiation model system, normal human breast epithelial putative stem cells, to study the potential role of GJ's in differentiation in order to link the blockage of GJIC and differentiation in carcinogenesis. Logic tree of this application is that GJIC in a multicellular organism is obligatory for the regulation of cell proliferation and differentiation in solid tissues. Reversible modulation of GJIC is done by extracellular communication signals which could trigger signal transduction within a cell to modulate GJ's at the transcriptional, translational or post- translational levels in normal cells. Cancer, a disease of cell proliferation and differentiation, would appear to have been blocked somewhere in the link between extra-, intra- and GJIC-intercellular communication. The proposed studies are designed to test this hypothesis.