The reversibility of mitotic exit in vertebrate cells

Nature. 2006 Apr 13;440(7086):954-8. doi: 10.1038/nature04652.


A guiding hypothesis for cell-cycle regulation asserts that regulated proteolysis constrains the directionality of certain cell-cycle transitions. Here we test this hypothesis for mitotic exit, which is regulated by degradation of the cyclin-dependent kinase 1 (Cdk1) activator, cyclin B. Application of chemical Cdk1 inhibitors to cells in mitosis induces cytokinesis and other normal aspects of mitotic exit, including cyclin B degradation. However, chromatid segregation fails, resulting in entrapment of chromatin in the midbody. If cyclin B degradation is blocked with a proteasome inhibitor or by expression of non-degradable cyclin B, Cdk inhibitors will nonetheless induce mitotic exit and cytokinesis. However, if after mitotic exit, the Cdk1 inhibitor is washed free from cells in which cyclin B degradation is blocked, the cells can revert back to M phase. This reversal is characterized by chromosome recondensation, nuclear envelope breakdown, assembly of microtubules into a mitotic spindle, and in most cases, dissolution of the midbody, reopening of the cleavage furrow, and realignment of chromosomes at the metaphase plate. These findings demonstrate that proteasome-dependent degradation of cyclin B provides directionality for the M phase to G1 transition.

Publication types

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

MeSH terms

  • Animals
  • CDC2 Protein Kinase / antagonists & inhibitors
  • CDC2 Protein Kinase / metabolism
  • Cell Line
  • Cells, Cultured
  • Cyclin B / metabolism
  • Cytokinesis / drug effects
  • Flavonoids / pharmacology
  • G1 Phase / drug effects
  • HeLa Cells
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Keratinocytes / enzymology
  • Keratinocytes / metabolism
  • Metaphase / drug effects
  • Mitosis / drug effects
  • Mitosis / physiology*
  • Models, Biological
  • Nocodazole / pharmacology
  • Piperidines / pharmacology
  • Proteasome Endopeptidase Complex / metabolism
  • Xenopus*


  • Cyclin B
  • Flavonoids
  • Piperidines
  • alvocidib
  • CDC2 Protein Kinase
  • Proteasome Endopeptidase Complex
  • Nocodazole