2005 Fiscal Year Final Research Report Summary
Studies on the signal transduction pathway of differentiation inducing factor to induce cyclin D1 degradation
| Project/Area Number |
16590198
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
TAKAHASHI Fumi Kyushu University, Graduate School of Medical Sciences, Clinical Pharmacology, Research Associate, 大学院・医学研究院, 助手 (50274436)
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| Co-Investigator(Kenkyū-buntansha) |
WATANABE Yutaka Ehime University, Faculty of Engneering Dept of Applied Chemistry, Professor, 工学部, 教授 (40114722)
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| Project Period (FY) |
2004 – 2005
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| Keywords | antiproliferation / cancer / cyclin D1 / cell cycle |
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| Research Abstract |
Differentiation-inducing factors (DIFs) are putative morphogens that induce cell differentiation in Dictyostelium discoideum. We reported that DIF-3 activates glycogen synthase kinase-3β (GSK-3β), resulting in the degradation of cyclin D1 in HeLa cells. In this study, we investigated the effect of DIF-3 on cyclin D1 mutants (Arg29Gln, Leu32Ala, Thr286Ala, Thr288Ala and Thr286/288Ala) to clarify the precise mechanisms by which DIF-3 degrades cyclin D1 in HeLa cells. We revealed that Thr286Ala, Thr288Ala, and Thr286/288Ala mutants were resistant to DIF-3-induced degradation compared with wild-type cyclin D1, indicating that the phosphorylation of Thr^<286> and Thr^<288> were critical for cyclin D1 degradation induced by DIF-3. Indeed, DIF-3 markedly elevated the phosphorylation level of cyclin D1, and mutations introduced to Thr^<286> and/or Thr^<288> prevented the phosphorylation induced by DIF-3. Depletion of endogenous GSK-3β and dual-specificity tyrosine-phosphorylation regulated kinase 1B (DYRK1B) by RNA interference attenuated the DIF-3-induced cyclin D1 phosphorylation and degradation. These results suggest that DIF-3 induces degradation of cyclin D1 through the GSK-3β- and DYRK1B-mediated threonine phosphorylation.
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