Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process.
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.
Lordier
Larissa
L
INSERM U1009, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, France.
Chang
Yunhua
Y
Jalil
Abdelali
A
Aurade
Frédéric
F
Garçon
Loïc
L
Lécluse
Yann
Y
Larbret
Frédéric
F
Kawashima
Toshiyuki
T
Kitamura
Toshio
T
Larghero
Jérôme
J
Debili
Najet
N
Vainchenker
William
W
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D064107:Aurora Kinase B; D064127:Aurora Kinases; D020090:Chromosome Segregation / Q000187:drug effects / Q000502:physiology; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D051034:Inhibitor of Apoptosis Proteins; D008533:Megakaryocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D008941:Spindle Apparatus / Q000201:enzymology; D000077022:Survivin
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D047428:Protein Kinase Inhibitors; D000077022:Survivin; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases