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Studies on the signal transduction pathway of differentiation inducing factor to induce cyclin D1 degradation

分化诱导因子诱导cyclin D1降解的信号转导途径研究

基本信息

批准号：
16590198
负责人：
TAKAHASHI Fumi
金额：
$ 2.24万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590198/
关键词：
antiproliferation cancer cyclin D1 cell cycle 細胞周期拘束

项目摘要

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.

分化诱导因子（DIF）是诱导盘基网柄藻细胞分化的形态发生因子。我们报道了DIF-3激活糖原合成酶激酶-3 β（GSK-3β），导致HeLa细胞中细胞周期蛋白D1的降解。在这项研究中，我们研究了DIF-3对细胞周期蛋白D1突变体（Arg 29 Gln，Leu 32Ala，Thr 286 Ala，Thr 288 Ala和Thr 286/288 Ala）的影响，以阐明DIF-3降解HeLa细胞中细胞周期蛋白D1的确切机制。我们发现Thr 286 Ala、Thr 288 Ala和Thr 286/288 Ala突变体与野生型细胞周期蛋白D1相比对DIF-3诱导的降解具有抗性，这表明Thr^和Thr^的磷酸化<286><288>对于DIF-3诱导的细胞周期蛋白D1降解至关重要。事实上，DIF-3显著提高了细胞周期蛋白D1的磷酸化水平，并且引入Thr^<286>和/或Thr^<288>的突变阻止了DIF-3诱导的磷酸化。通过RNA干扰去除内源性GSK-3β和双特异性酪氨酸磷酸化调节激酶1B（DYRK 1B）可减弱DIF-3诱导的细胞周期蛋白D1磷酸化和降解。这些结果表明，DIF-3通过GSK-3β和DYRK 1B介导的苏氨酸磷酸化诱导细胞周期蛋白D1的降解。