Aurora B kinase regulates the postmitotic endoreduplication checkpoint via phosphorylation of the retinoblastoma protein at serine 780.
The phenotypic change characteristic of Aurora B inhibition is the induction of polyploidy. Utilizing specific siRNA duplexes and a selective small molecule inhibitor (AZD1152) to inhibit Aurora B activity in tumor cells, we sought to elucidate the mechanism by which Aurora B inhibition results in polyploidy. Cells treated with AZD1152 progressed through mitosis with misaligned chromosomes and exited without cytokinesis and subsequently underwent endoreduplication of DNA despite activation of a p53-dependent pseudo G1 checkpoint. Concomitant with polyploid cell formation, we observed the appearance of Rb hypophosphorylation, an event that occurred independently of cyclin-dependent kinase inhibition. We went on to discover that Aurora B directly phosphorylates Rb at serine 780 both in vitro and in vivo. This novel interaction plays a critical role in regulating the postmitotic checkpoint to prevent endoreduplication after an aberrant mitosis. Thus, we propose for the first time that Aurora B determines cellular fate after an aberrant mitosis by directly regulating the Rb tumor suppressor protein.
Nair
Jayasree S
JS
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Ho
Alan L
AL
Tse
Archie N
AN
Coward
Jesse
J
Cheema
Haider
H
Ambrosini
Grazia
G
Keen
Nicholas
N
Schwartz
Gary K
GK
D000595:Amino Acid Sequence; D064107:Aurora Kinase B; D064127:Aurora Kinases; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D008969:Molecular Sequence Data; D010755:Organophosphates / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism*; D011123:Polyploidy; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D006657:Histones; D010755:Organophosphates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D010768:Phosphoserine; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases