Active Transport Can Greatly Enhance Cdc20:Mad2 Formation

Int J Mol Sci. 2014 Oct 21;15(10):19074-91. doi: 10.3390/ijms151019074.

Abstract

To guarantee genomic integrity and viability, the cell must ensure proper distribution of the replicated chromosomes among the two daughter cells in mitosis.The mitotic spindle assembly checkpoint (SAC) is a central regulatory mechanism to achieve this goal. A dysfunction of this checkpoint may lead to aneuploidy and likely contributes to the development of cancer. Kinetochores of unattached or misaligned chromosomes are thought to generate a diffusible ''wait-anaphase'' signal, which is the basis for downstream events to inhibit the anaphase promoting complex/cyclosome (APC/C). The rate of Cdc20:C-Mad2 complex formation at the kinetochore is a key regulatory factor in the context of APC/C inhibition. Computer simulations of a quantitative SAC model show that the formation of Cdc20:C-Mad2 is too slow for checkpoint maintenance when cytosolic O-Mad2 has to encounter kinetochores by diffusion alone. Here, we show that an active transport of O-Mad2 towards the spindle mid-zone increases the efficiency of Mad2-activation. Our data indicate that this mechanism can greatly enhance the formation of Cdc20:Mad2 and furthermore gives an explanation on how the ''wait-anaphase'' signal can dissolve abruptly within a short time. Our results help to understand parts of the SAC mechanism that remain unclear.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome / genetics*
  • Biological Transport, Active / genetics*
  • Biological Transport, Active / physiology
  • Cdc20 Proteins / genetics*
  • Cell Cycle Proteins / genetics
  • Cytosol / physiology
  • Humans
  • Kinetochores / physiology*
  • M Phase Cell Cycle Checkpoints / genetics
  • M Phase Cell Cycle Checkpoints / physiology
  • Mad2 Proteins / genetics*
  • Mitosis / genetics
  • Mitosis / physiology*
  • Nuclear Proteins / genetics
  • Spindle Apparatus / genetics

Substances

  • Cdc20 Proteins
  • Cell Cycle Proteins
  • Mad2 Proteins
  • Nuclear Proteins
  • Anaphase-Promoting Complex-Cyclosome