Yasmin Tania, Takahashi-Yanaga Fumi, Mori Jun, Miwa Yoshikazu, Hirata Masato, Watanabe Yutaka, Morimoto Sachio, Sasaguri Toshiyuki
Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Biochem Biophys Res Commun. 2005 Dec 16;338(2):903-9. doi: 10.1016/j.bbrc.2005.10.018. Epub 2005 Oct 14.
To determine the mechanism by which differentiation-inducing factor-1 (DIF-1), a morphogen of Dictyostelium discoideum, inhibits tumor cell proliferation, we examined the effect of DIF-1 on the gene expression of cyclin D1. DIF-1 strongly reduced the expression of cyclin D1 mRNA and correspondingly decreased the amount of beta-catenin in HeLa cells and squamous cell carcinoma cells. DIF-1 activated glycogen synthase kinase-3beta (GSK-3beta) and inhibition of GSK-3beta attenuated the DIF-1-induced beta-catenin degradation, indicating the involvement of GSK-3beta in this effect. Moreover, DIF-1 reduced the activities of T-cell factor (TCF)/lymphoid enhancer factor (LEF) reporter plasmid and a reporter gene driven by the human cyclin D1 promoter. Eliminating the TCF/LEF consensus site from the cyclin D1 promoter diminished the effect of DIF-1. These results suggest that DIF-1 inhibits Wnt/beta-catenin signaling, resulting in the suppression of cyclin D1 promoter activity.
为了确定盘基网柄菌的形态发生素分化诱导因子-1（DIF-1）抑制肿瘤细胞增殖的机制，我们研究了DIF-1对细胞周期蛋白D1基因表达的影响。DIF-1显著降低了HeLa细胞和鳞状细胞癌细胞中细胞周期蛋白D1 mRNA的表达，并相应减少了β-连环蛋白的量。DIF-1激活了糖原合酶激酶-3β（GSK-3β），抑制GSK-3β可减弱DIF-1诱导的β-连环蛋白降解，表明GSK-3β参与了这一效应。此外，DIF-1降低了T细胞因子（TCF）/淋巴细胞增强因子（LEF）报告质粒以及由人细胞周期蛋白D1启动子驱动的报告基因的活性。从细胞周期蛋白D1启动子中去除TCF/LEF共有位点可减弱DIF-1的作用。这些结果表明，DIF-1抑制Wnt/β-连环蛋白信号传导，从而导致细胞周期蛋白D1启动子活性受到抑制。
