MTBP plays a crucial role in mitotic progression and chromosome segregation

Cell Death Differ. 2011 Jul;18(7):1208-19. doi: 10.1038/cdd.2010.189. Epub 2011 Jan 28.

Abstract

Murine double minute 2 (MDM2) binding protein (MTBP) has been implicated in tumor cell proliferation, but the underlying mechanisms remain unclear. The results of MTBP expression analysis during cell cycle progression demonstrated that MTBP protein was rapidly degraded during mitosis. Immunofluorescence studies revealed that a portion of MTBP was localized at the kinetochores during prometaphase. MTBP overexpression delayed mitotic progression from nuclear envelope breakdown (NEB) to anaphase onset and induced abnormal chromosome segregation such as lagging chromosomes, chromosome bridges, and multipolar chromosome segregation. Conversely, MTBP downmodulation caused an abbreviated metaphase and insufficient mitotic arrest, resulting in abnormal chromosome segregation, aneuploidy, decreased cell proliferation, senescence, and cell death, similar to that of Mad2 (mitotic arrest-deficient 2) downmodulation. Furthermore, MTBP downmodulation inhibited the accumulation of Mad1 and Mad2, but not BubR1 (budding uninhibited by benzimidazoles related 1), on the kinetochores, whereas MTBP overexpression inhibited the release of Mad2 from the metaphase kinetochores. These results may imply that MTBP has an important role in recruiting and/or retaining the Mad1/Mad2 complex at the kinetochores during prometaphase, but its degradation is required for silencing the mitotic checkpoint. Together, this study indicates that MTBP has a crucial role in proper mitotic progression and faithful chromosome segregation, providing new insights into regulation of the mitotic checkpoint.

Publication types

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

MeSH terms

  • Aneuploidy
  • Apoptosis
  • Calcium-Binding Proteins / metabolism
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cellular Senescence
  • Chromosome Segregation*
  • Humans
  • Kinetochores / metabolism
  • Mad2 Proteins
  • Metaphase
  • Mitosis*
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Repressor Proteins / metabolism

Substances

  • Calcium-Binding Proteins
  • Carrier Proteins
  • Cell Cycle Proteins
  • MAD2L1 protein, human
  • MTBP protein, human
  • Mad2 Proteins
  • RNA, Small Interfering
  • Repressor Proteins
  • BUB1 protein, human
  • Bub1 spindle checkpoint protein
  • Protein-Serine-Threonine Kinases