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.
Mesh Terms:
Amino Acid Sequence, HCT116 Cells, Histones, Humans, Mitosis, Molecular Sequence Data, Phosphoric Acid Esters, Phosphorylation, Phosphoserine, Polyploidy, Protein Binding, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Quinazolines, Retinoblastoma Protein, Tumor Suppressor Protein p53
Amino Acid Sequence, HCT116 Cells, Histones, Humans, Mitosis, Molecular Sequence Data, Phosphoric Acid Esters, Phosphorylation, Phosphoserine, Polyploidy, Protein Binding, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Quinazolines, Retinoblastoma Protein, Tumor Suppressor Protein p53
Mol. Biol. Cell
Date: Apr. 01, 2009
PubMed ID: 19225156
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