Two Distinct Controls of Mitotic Cdk1/Cyclin B1 Activity Requisite for Cell Growth Prior to Cell Division
Two Distinct Controls of Mitotic Cdk1/Cyclin B1 Activity Requisite for Cell Growth Prior to Cell Division
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DOI：
10.4161/cc.6.12.4409
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发表时间：
2007-06
期刊：
影响因子：
4.3
通讯作者：
T. Miyazaki;S. Arai
中科院分区：
文献类型：
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作者：
T. Miyazaki;S. Arai
细胞分裂前的细胞生长受到细胞周期蛋白依赖性激酶1 (Cdk1)/细胞周期蛋白B1复合物活性的限制。最近，我们发现含有死亡效应结构域（DED）的蛋白，DEDD，作为有丝分裂Cdk1/细胞周期蛋白B1的一种新型抑制剂，影响细胞大小。与细胞周期蛋白B1一样，DEDD蛋白水平在G2/M期达到峰值。在细胞核中，DEDD通过直接结合细胞周期蛋白B1与Cdk1/cyclin B1复合物结合，并降低其功能。与此一致的是，与DEDD+/+细胞相比，细胞核Cdk1/cyclin B1在DEDD-null （DEDD-/-）胚胎成纤维细胞中的激酶活性增加。这加速了DEDD-/-细胞的有丝分裂进程，G2/M期缩短，rRNA减少，细胞体积减小。同样，与DEDD+/+小鼠相比，DEDD-/-小鼠的身体和器官重量也有所减轻。有趣的是，DED结构域不参与DEDD与Cdk1/cyclin B1的关联，但对于DEDD的细胞大小功能是不可或缺的。总之，除了通过其抑制残基的去磷酸化激活Cdk1的完善机制外，我们还提出了一种新的机制，用于细胞核内由DEDD介导的有丝分裂Cdk1/cyclin B1的障碍调节，该机制允许在细胞分裂之前充分的细胞生长。
Cell growth prior to cell division is restricted by the activity of cyclin-dependent kinase 1 (Cdk1)/cyclin B1 complexes. Recently, we identified that the death-effector domain (DED) containing protein, DEDD, acts as a novel inhibitor of mitotic Cdk1/cyclin B1, influencing cell size. Like cyclin B1, DEDD protein levels specifically peak during the G2/M phase. In the nucleus, DEDD associates with Cdk1/cyclin B1 complexes, via direct binding to cyclin B1, and reduces their function. In agreement, kinase activity of nuclear Cdk1/cyclin B1 in DEDD-null (DEDD-/-) embryonic fibroblasts is increased compared to that in DEDD+/+ cells. This accelerates mitotic progression in DEDD-/- cells, with a shortened G2/M phase, reduced rRNA, and diminished cell volume. Likewise, DEDD-/- mice show decreased body and organ weights relative to DEDD+/+ mice. Interestingly, the DED domain is not involved in the association of DEDD with Cdk1/cyclin B1, but is indispensable for the cell sizing function of DEDD. Together, in addition to the well-established machinery for activation of Cdk1 through dephosphorylation of its inhibitory-residues, we propose a novel mechanism for impeditive regulation of mitotic Cdk1/cyclin B1 mediated by DEDD within the nucleus, which allows sufficient cell growth prior to cell division.