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

Hai Jiang, Jianchun Wu, Chen He, Wending Yang, Honglin Li

Research output: Contribution to journalArticle

25 Citations (Scopus)

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-B 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.

Original languageEnglish (US)
Pages (from-to)458-468
Number of pages11
JournalCell Research
Volume19
Issue number4
DOIs
StatePublished - Apr 1 2009

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CDC2 Protein Kinase
Tumor Suppressor Proteins
Phosphotransferases
DNA Damage
Centrosome
Checkpoint Kinase 2
Proteins
Cyclin B1
Cell Cycle
Cell Death
Neoplasms

Keywords

  • C53
  • Cdk1
  • Checkpoint kinases

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Tumor suppressor protein C53 antagonizes checkpoint kinases to promote cyclin-dependent kinase 1 activation. / Jiang, Hai; Wu, Jianchun; He, Chen; Yang, Wending; Li, Honglin.

In: Cell Research, Vol. 19, No. 4, 01.04.2009, p. 458-468.

Research output: Contribution to journalArticle

Jiang, Hai ; Wu, Jianchun ; He, Chen ; Yang, Wending ; Li, Honglin. / Tumor suppressor protein C53 antagonizes checkpoint kinases to promote cyclin-dependent kinase 1 activation. In: Cell Research. 2009 ; Vol. 19, No. 4. pp. 458-468.
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