GAP JUNCTIONAL COMMUNICATION AND TRANSFORMATION

间隙连接是在接触区域形成的质膜结构 相邻细胞之间。 连接点由数百到数千个 每个蛋白质颗粒都含有一个微小的（1.5-2 nm）孔 连接相邻细胞的细胞质。 通过这些渠道流动 小的（小于1,000 Da）离子和分子。 这种化学品运输是 称为间隙连接细胞间通讯（GJIC）及其 功能了解不多。 许多间接证据表明， 这表明GJIC的缺失在某种程度上促进了细胞生长 和转化表型的表达。 GJIC受到抑制， 某些致癌物质，生长促进剂和转化，但增强 抗癌剂、生长抑制剂、分化剂， 在转化表型逆转之后。 本 建议，这一假设将以直接的方式处理。 GJIC 在非转化细胞中，通过阻止 通过转染表达差距连接通道形成蛋白 反义DNA 这些细胞的生长速度和对 改革将被量化，并应得到加强。 GJIC还将 在转化细胞中通过转染 细胞间隙连接蛋白cDNA。 这些细胞的致瘤性 将被确定，它们应该是较低的致瘤性。 此外该 DDT（GJIC抑制剂）促进生长的能力， 将对转型进行评估。 激活ras的机制 将确定癌基因表达和DDT减少GJIC。 这些 研究将提供直接证据支持或反对GJIC在以下方面的作用： 细胞转化，并可能表明可能使用的临床 旨在增强GJIC的抗肿瘤疗法。

Gap junctions are plasma membrane structures formed at regions of contact between adjacent cells. The junctions consist of hundreds to thousands of proteinaceous particles that each contain a tiny (1.5-2 nm) pore linking the cytoplasm of the adjacent cells. Through these channels flow small (less than 1,000 Da) ions and molecules. This chemical traffic is known as gap junctional intercellular communication (GJIC) and its functions are poorly understood. Much indirect evidence has led to the suggestion that the loss of GJIC in some way facilitates cellular growth and expression of the transformed phenotype. GJIC is inhibited-by certain carcinogens, growth enhancers, and transformation but is enhanced by anticarcinogens, growth inhibitors, differentiating agents, and following reversal of the transformed phenotype. In the present proposal, this hypothesis will be addressed in a direct manner. GJIC will be specifically inhibited in nontransformed cells by preventing the expression of the gap junction channel-forming protein by transfection with antisense DNA. The growth rate and sensitivity of these cells to transformation will be quantified and should be enhanced. GJIC will also be specifically increased in transformed cells by transfection of the cells with gap junction protein cDNA. The tumorigenicity of these cells will be determined and they should be less tumorigenic. In addition, the ability of DDT, an inhibitor of GJIC, to enhance growth and transformation will be assessed. The mechanisms by which activated ras oncogene expression and DDT reduce GJIC will be determined. These studies will provide direct evidence for or against a role of GJIC in cellular transformation and may suggest the possible use of clinical antitumor therapies designed to enhance GJIC.