Cell Death by Mitotic Catastrophe: A Molecular Definition

Oncogene. 2004 Apr 12;23(16):2825-37. doi: 10.1038/sj.onc.1207528.

Abstract

The current literature is devoid of a clearcut definition of mitotic catastrophe, a type of cell death that occurs during mitosis. Here, we propose that mitotic catastrophe results from a combination of deficient cell-cycle checkpoints (in particular the DNA structure checkpoints and the spindle assembly checkpoint) and cellular damage. Failure to arrest the cell cycle before or at mitosis triggers an attempt of aberrant chromosome segregation, which culminates in the activation of the apoptotic default pathway and cellular demise. Cell death occurring during the metaphase/anaphase transition is characterized by the activation of caspase-2 (which can be activated in response to DNA damage) and/or mitochondrial membrane permeabilization with the release of cell death effectors such as apoptosis-inducing factor and the caspase-9 and-3 activator cytochrome c. Although the morphological aspect of apoptosis may be incomplete, these alterations constitute the biochemical hallmarks of apoptosis. Cells that fail to execute an apoptotic program in response to mitotic failure are likely to divide asymmetrically in the next round of cell division, with the consequent generation of aneuploid cells. This implies that disabling of the apoptotic program may actually favor chromosomal instability, through the suppression of mitotic catastrophe. Mitotic catastrophe thus may be conceived as a molecular device that prevents aneuploidization, which may participate in oncogenesis. Mitotic catastrophe is controlled by numerous molecular players, in particular, cell-cycle-specific kinases (such as the cyclin B1-dependent kinase Cdk1, polo-like kinases and Aurora kinases), cell-cycle checkpoint proteins, survivin, p53, caspases and members of the Bcl-2 family.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Apoptosis*
  • CDC2 Protein Kinase / physiology
  • Cell Cycle Proteins / physiology
  • Checkpoint Kinase 2
  • Cyclin B / physiology
  • Cyclin B1
  • DNA Damage
  • Humans
  • Mitosis*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Polyploidy
  • Protein-Serine-Threonine Kinases / physiology
  • Tumor Suppressor Protein p53 / physiology
  • Xenopus Proteins / physiology

Substances

  • CCNB1 protein, human
  • Cell Cycle Proteins
  • Cyclin B
  • Cyclin B1
  • Tumor Suppressor Protein p53
  • Xenopus Proteins
  • PlK2 protein, Xenopus
  • Checkpoint Kinase 2
  • CHEK2 protein, human
  • Protein-Serine-Threonine Kinases
  • CDC2 Protein Kinase