GAP JUNCTIONAL COMMUNICATION AND TRANSFORMATION

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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.