Studies on the signal transduction of difrentiation inducing factor and an application for the development of anti-cancer drug for early G_1 phase.

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Differentiation-inducing factors (DIFs) are morphogens which induce cell differentiation in Dictyostelium. However, the effect of the DIF family is not limited in Dictyostelium. DIF-1 and/or DIF-3 strongly inhibit cell proliferation and induce cell differentiation in several mammalian cells. We therefore investigated the mechanisms for the antiproliferative action of DIFs in mammalian cells.We found that DIFs (DIF-1 and DIF-3) activates GSK-3β to accelerate the proteolysis of cyclin D1 and this mechanism is involved in the DIFs-induced G_0/G_1 arrest in mammalian cells. We next examined the effect of DIFs on cyclin D1 mutants and found that the phosphorylation of Thr^<286> was critical for cyclin D1 degradation induced by DIFs. These findings suggest that DIF-1 induces degradation of cyclin D1 through the GSK-3β-mediated phosphorylation of Thr^<286>. Moreover, we tried to identify the mechanism for the DIF-1-induced suppression of cyclin D1 mRNA expression and found that DIF-1 induces GSK-3β-mediaged degradation of β-catenin, resulting in the suppression of TCF/LEF transcriptional activity in the cyclin D1 promoter.Further, we tried to identify a kinase which induce phosphorylation on Tyr^<216> in GSK-3β and suggested that MEK1/2 induces tyrosine phosphorylation of GSK-3β and this cellular event might induce nuclear translocation of GSK-3β.