Studies on the signal transduction of difrentiation inducing factor and an application for the development of anti-cancer drug for early G_1 phase.
| Project/Area Number |
14370034
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
General pharmacology
|
|---|
| Research Institution | Kyushu University |
|---|
Principal Investigator |
SASAGURI Toshiyuki KYUSHU UNIVERSITY, Graduate School of Medical Sciences, Clinical Pharmacology, Professor, 大学院・医学研究院, 教授 (30261209)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Fumi (YANAGA Fumi) KYUSHU UNIVERSITY, Graduate School of Medical Sciences, Clinical Pharmacology, Research Associate, 大学院・医学研究院, 助手 (50274436)
|
|---|
| Project Period (FY) |
2002 – 2004
|
| Project Status |
Completed (Fiscal Year 2004)
|
| Budget Amount *help |
¥10,500,000 (Direct Cost: ¥10,500,000)
Fiscal Year 2004: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2003: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2002: ¥4,700,000 (Direct Cost: ¥4,700,000)
|
|---|
| Keywords | antiproliferation / cancer / cyclin D1 / cell cycle |
|---|
| Research Abstract |
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.
|
Report
(4 results)
Research Products
(6 results)
