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 by way of inhibiting NF-kappaB signaling. We report here the 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 overexpression. Intriguingly, we found that C53 interacts with 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.
Jiang
Hai
H
Children's Memorial Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60614, USA.
Wu
Jianchun
J
He
Chen
C
Yang
Wending
W
Li
Honglin
H
D016203:CDC2 Protein Kinase / Q000378:metabolism*; D018797:Cell Cycle Proteins; D016923:Cell Death; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D019926:Cyclin B; D056744:Cyclin B1; D004249:DNA Damage; D016195:G2 Phase; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008938:Mitosis; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D034622:RNA Interference; D025521:Tumor Suppressor Proteins
C534699:CCNB1 protein, human; C405928:CDK5RAP3 protein, human; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D016203:CDC2 Protein Kinase