Tumor suppressor protein C53 antagonizes checkpoint kinases to promote cyclin-dependent kinase 1 activation.

Cyclin dependent kinase 1 (Cdk1)/cyclin B1 complex is the driving force for mitotic entry, and its activation is tightly regulated by the G2/M checkpoint. We originally reported that a novel protein C53 (also known as Cdk5rap3 and LZAP) potentiates DNA damage-induced cell death by modulating the G2/M checkpoint. More recently, Wang et al (2007) found that C53/LZAP may function as a tumor suppressor via inhibiting NF-κB signaling. We report here identification of C53 protein as a novel regulator of Cdk1 activation. We found that knockdown of C53 protein causes delayed Cdk1 activation and mitotic entry. During DNA damage response, activation of checkpoint kinase 1 and 2 (Chk1 and Chk2) is partially inhibited by C53 overexrepsssion. Intriguingly, we found that C53 interacts with checkpoint kinase 1 (Chk1) and antagonizes its function. Moreover, a portion of C53 protein is localized at the centrosome, and centrosome-targeting C53 potently promotes local Cdk1 activation. Taken together, our results strongly suggest that C53 is a novel negative regulator of checkpoint response. By counteracting Chk1, C53 promotes Cdk1 activation and mitotic entry in both unperturbed cell cycle progression and DNA damage response.

细胞周期蛋白依赖性激酶1（Cdk1）/细胞周期蛋白B1复合物是有丝分裂进入的驱动力，其激活受到G2/M检查点的严格调控。我们先前报道一种新型蛋白质C53（也称为Cdk5rap3和LZAP）通过调节G2/M检查点增强DNA损伤诱导的细胞死亡。最近，Wang等人（2007年）发现C53/LZAP可能通过抑制NF - κB信号传导发挥肿瘤抑制作用。我们在此报道将C53蛋白鉴定为Cdk1激活的一种新型调节因子。我们发现C53蛋白的敲低导致Cdk1激活和有丝分裂进入延迟。在DNA损伤反应过程中，检查点激酶1和2（Chk1和Chk2）的激活被C53过表达部分抑制。有趣的是，我们发现C53与检查点激酶1（Chk1）相互作用并拮抗其功能。此外，一部分C53蛋白定位于中心体，靶向中心体的C53有力地促进局部Cdk1激活。综上所述，我们的结果强烈表明C53是检查点反应的一种新型负调节因子。通过对抗Chk1，C53在未受干扰的细胞周期进程和DNA损伤反应中促进Cdk1激活和有丝分裂进入。