Analysis of the mechanisms of the actions of DIF-1 and its derivatives, anti-tumor agents isolated from Dictyostelium

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The cellular slime mould Dictyostelium discoideum is thought to be an excellent model organism for the study of cell and developmental biology because of its simple pattern of development. The differentiation-inducing factor-1 (DIF-1) was originally identified as signal molecules that induce stalk cell differentiation in D.discoideum. On the other hand, we have shown that DIF-1 exhibits strong anti-proliferative activities and occasionally induce cell differentiation in mammalian cells. Furthermore, we have shown that calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) is a pharmacological and specific target of DIF-1. Yet, the mechanisms underlying the actions of DIF-1 in mammalian cells remain to be elucidated.In the present study;1.We synthesized 30 DIF derivatives, and analyzed their chemical structure-effect relationship in vitro, and found some potent anti-tumor agents.2.We are attempting to isolate DIF-resistant HEK293 cell lines, using RNAi technique, to elucidate the mechanism of the action of DIFs.3.During the course of the study on DIF toxicity, we have found that DIF-1 promote glucose metabolism in mammalian cells.4.We have shown that DIF-1 induces stalk cell formation via increases in cytoplasmic calcium and proton in Dictyostelium discoideum.5.We have isolated several new substances that have pharmacological activities.6.We happened to find that zinc ions inhibit calcineurin activity in vitro and shown that zinc ions suppress mitogen-activated IL-2 production in Jurkat T cell.