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

Cell Res. 2009 Apr;19(4):458-68. doi: 10.1038/cr.2009.14.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CDC2 Protein Kinase / metabolism*
  • Cell Cycle Proteins
  • Cell Death
  • Cell Line
  • Centrosome / metabolism
  • 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 / metabolism*
  • Mitosis
  • NF-kappa B / metabolism
  • Nerve Tissue Proteins / metabolism*
  • Protein Kinases / metabolism*
  • RNA Interference
  • Tumor Suppressor Proteins

Substances

  • CCNB1 protein, human
  • CDK5RAP3 protein, human
  • Cell Cycle Proteins
  • Cyclin B
  • Cyclin B1
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Nerve Tissue Proteins
  • Tumor Suppressor Proteins
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • CDC2 Protein Kinase