Cyclin-dependent kinase 1 （Cdkl）/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...Cyclin-dependent kinase 1 （Cdkl）/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 by way of inhibiting NF-kB signaling. We re- port here the identification of C53 protein as a novel regulator of Cdkl activation. We found that knockdown of C53 protein causes delayed Cdkl activation and mitotic entry. During DNA damage response, activation of checkpoint kinase 1 and 2 （Chkl and Chk2） is partially inhibited by C53 overexpression. Intriguingly, we found that C53 inter- acts with Chkl and antagonizes its function. Moreover, a portion of C53 protein is localized at the centrosome, and centrosome-targeting C53 potently promotes local Cdkl activation. Taken together, our results strongly suggest that C53 is a novel negative regulator of checkpoint response. By counteracting Chkl, C53 promotes Cdkl activation and mitotic entry in both unperturbed cell-cycle progression and DNA damage response.展开更多
文摘Cyclin-dependent kinase 1 （Cdkl）/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 by way of inhibiting NF-kB signaling. We re- port here the identification of C53 protein as a novel regulator of Cdkl activation. We found that knockdown of C53 protein causes delayed Cdkl activation and mitotic entry. During DNA damage response, activation of checkpoint kinase 1 and 2 （Chkl and Chk2） is partially inhibited by C53 overexpression. Intriguingly, we found that C53 inter- acts with Chkl and antagonizes its function. Moreover, a portion of C53 protein is localized at the centrosome, and centrosome-targeting C53 potently promotes local Cdkl activation. Taken together, our results strongly suggest that C53 is a novel negative regulator of checkpoint response. By counteracting Chkl, C53 promotes Cdkl activation and mitotic entry in both unperturbed cell-cycle progression and DNA damage response.
