Mikule Keith, Delaval Benedicte, Kaldis Philipp, Jurcyzk Agata, Hergert Polla, Doxsey Stephen
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Nat Cell Biol. 2007 Feb;9(2):160-70. doi: 10.1038/ncb1529.
Centrosomes organize the microtubule cytoskeleton for both interphase and mitotic functions. They are implicated in cell-cycle progression but the mechanism is unknown. Here, we show that depletion of 14 out of 15 centrosome proteins arrests human diploid cells in G1 with reduced Cdk2-cyclin A activity and that expression of a centrosome-disrupting dominant-negative construct gives similar results. Cell-cycle arrest is always accompanied by defects in centrosome structure and function (for example, duplication and primary cilia assembly). The arrest occurs from within G1, excluding contributions from mitosis and cytokinesis. The arrest requires p38, p53 and p21, and is preceded by p38-dependent activation and centrosomal recruitment of p53. p53-deficient cells fail to arrest, leading to centrosome and spindle dysfunction and aneuploidy. We propose that loss of centrosome integrity activates a checkpoint that inhibits G1-S progression. This model satisfies the definition of a checkpoint in having three elements: a perturbation that is sensed, a transducer (p53) and a receiver (p21).
中心体为间期和有丝分裂功能组织微管细胞骨架。它们与细胞周期进程有关，但机制尚不清楚。在这里，我们表明15种中心体蛋白中的14种缺失会使人类二倍体细胞停滞在G1期，Cdk2-细胞周期蛋白A活性降低，并且破坏中心体的显性负性构建体的表达也产生类似结果。细胞周期停滞总是伴随着中心体结构和功能的缺陷（例如，复制和初级纤毛组装）。停滞发生在G1期内，排除了有丝分裂和胞质分裂的影响。停滞需要p38、p53和p21，并且在p38依赖的p53激活和中心体募集之前发生。p53缺陷细胞无法停滞，导致中心体和纺锤体功能障碍以及非整倍体。我们提出中心体完整性的丧失会激活一个抑制G1-S进程的检查点。该模型满足检查点的定义，具有三个要素：被感知的扰动、传感器（p53）和接收器（p21）。
