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.
Mesh Terms:
CDC2 Protein Kinase, Cell Cycle Proteins, Cell Death, Cell Line, Centrosome, Checkpoint Kinase 1, Cyclin B, Cyclin B1, DNA Damage, G2 Phase, Gene Expression Regulation, Gene Knockdown Techniques, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Mitosis, NF-kappa B, Nerve Tissue Proteins, Protein Kinases, RNA Interference, Tumor Suppressor Proteins
CDC2 Protein Kinase, Cell Cycle Proteins, Cell Death, Cell Line, Centrosome, Checkpoint Kinase 1, Cyclin B, Cyclin B1, DNA Damage, G2 Phase, Gene Expression Regulation, Gene Knockdown Techniques, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Mitosis, NF-kappa B, Nerve Tissue Proteins, Protein Kinases, RNA Interference, Tumor Suppressor Proteins
Cell Res
Date: Apr. 01, 2009
PubMed ID: 19223857
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