Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process

Blood. 2010 Sep 30;116(13):2345-55. doi: 10.1182/blood-2010-01-265785. Epub 2010 Jun 14.

Abstract

Polyploidization of megakaryocytes (MKs), the platelet precursors, occurs by endomitosis, a mitotic process that fails at late stages of cytokinesis. Expression and function of Aurora B kinase during endomitosis remain controversial. Here, we report that Aurora B is normally expressed during the human MK endomitotic process. Aurora B localized normally in the midzone or midbody during anaphase and telophase in low ploidy megakaryocytes and in up to 16N rare endomitotic MKs was observed. Aurora B was also functional during cytokinesis as attested by phosphorylation of both its activation site and MgcRacGAP, its main substrate. However, despite its activation, Aurora B did not prevent furrow regression. Inhibition of Aurora B by AZD1152-HQPA decreased cell cycle entry both in 2N to 4N and polyploid MKs and induced apoptosis mainly in 2N to 4N cells. In both MK classes, AZD1152-HQPA induced p53 activation and retinoblastoma hypophosphorylation. Resistance of polyploid MKs to apoptosis correlated to a high BclxL level. Aurora B inhibition did not impair MK polyploidization but profoundly modified the endomitotic process by inducing a mis-segregation of chromosomes and a mitotic failure in anaphase. This indicates that Aurora B is dispensable for MK polyploidization but is necessary to achieve a normal endomitotic process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Aurora Kinase B
  • Aurora Kinases
  • Chromosome Segregation / drug effects
  • Chromosome Segregation / physiology
  • G1 Phase / drug effects
  • G1 Phase / physiology
  • Humans
  • In Vitro Techniques
  • Inhibitor of Apoptosis Proteins
  • Megakaryocytes / cytology*
  • Megakaryocytes / drug effects
  • Megakaryocytes / enzymology*
  • Microtubule-Associated Proteins / metabolism
  • Mitosis / drug effects
  • Mitosis / genetics*
  • Mitosis / physiology*
  • Polyploidy*
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / physiology*
  • S Phase / drug effects
  • S Phase / physiology
  • Spindle Apparatus / enzymology
  • Survivin

Substances

  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Protein Kinase Inhibitors
  • Survivin
  • AURKB protein, human
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases