Aurora B prevents delayed DNA replication and premature mitotic exit by repressing p21(Cip1)

Cell Cycle. 2013 Apr 1;12(7):1030-41. doi: 10.4161/cc.24004. Epub 2013 Feb 21.

Abstract

Aurora kinase B is a critical component of the chromosomal passenger complex, which is involved in the regulation of microtubule-kinetochore attachments and cytokinesis. By using conditional knockout cells and chemical inhibition, we show here that inactivation of Aurora B results in delayed G(1)/S transition and premature mitotic exit. Aurora B deficiency results in delayed DNA replication in cultured fibroblasts as well as liver cells after hepatectomy. This is accompanied by increased transcription of the cell cycle inhibitor p21 (Cip1). Lack of Aurora B does not prevent mitotic entry but results in a premature exit from prometaphase in the presence of increased p21(Cip1)-Cdk1 inactive complexes. Aurora B-null cells display reduced degradation of cyclin B1, suggesting the presence of phenomenon known as adaptation to the mitotic checkpoint, previously described in yeast. Elimination of p21(Cip1) rescues Cdk1 activity and prevents premature mitotic exit in Aurora B-deficient cells. These results suggest that Aurora B represses p21(Cip1), preventing delayed DNA replication, Cdk inhibition and premature mitotic exit. The upregulation of p21(Cip1) observed after inhibition of Aurora B may have important implications in cell cycle progression, tetraploidy, senescence or cancer therapy.

Keywords: Aurora kinase B; G1/S progression; cancer target; mitosis; spindle assembly checkpoint.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aurora Kinase B
  • Aurora Kinases
  • CDC2 Protein Kinase / metabolism
  • Cell Line
  • Cyclin B1 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / antagonists & inhibitors
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • DNA Replication
  • G1 Phase Cell Cycle Checkpoints
  • Interphase
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitosis*
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism

Substances

  • Cyclin B1
  • Cyclin-Dependent Kinase Inhibitor p21
  • RNA, Small Interfering
  • Aurkb protein, mouse
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • CDC2 Protein Kinase