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

盘基网柄菌因其简单的发育模式而被认为是研究细胞和发育生物学的优秀模式生物。分化诱导因子-1(DIF-1)最初被鉴定为诱导盘藻茎细胞分化的信号分子。另一方面，我们发现DIF-1在哺乳动物细胞中表现出很强的抗增殖活性，偶尔也会诱导细胞分化。此外，我们还发现钙调素依赖的环核苷酸磷酸二酯酶(PDE1)是DIF-1的药理作用靶点和特异性靶点。然而，DIF-1在哺乳动物细胞中的作用机制仍有待阐明。1.我们合成了30个DIF衍生物，并对其进行了体外化学构效关系分析，发现了一些有效的抗肿瘤药物。2.我们试图利用RNAi技术分离耐DIF的HEK293细胞株，以阐明DIF的作用机制。3.在DIF毒性的研究过程中，我们发现DIF-1促进了哺乳动物细胞的葡萄糖代谢。4.我们发现DIF-1通过增加盘基网柄菌的胞内钙和质子来诱导柄细胞的形成。5.我们分离了几种新的具有药理活性的物质。6.我们在体外偶然发现锌离子抑制钙调神经磷酸酶的活性，并表明锌离子抑制Jurkat T细胞有丝分裂原激活的IL-2的产生。

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.