title: Aurora B prevents delayed DNA replication and premature mitotic exit by repressing p21(Cip1).
abstract: Aurora kinase B is a critical component of the chromosomal passenger complex, which is involved in the regulation of microtubule-kinetochore attachments and cytokinesis. By using conditional knockout cells and chemical inhibition, we show here that inactivation of Aurora B results in delayed G(1)/S transition and premature mitotic exit. Aurora B deficiency results in delayed DNA replication in cultured fibroblasts as well as liver cells after hepatectomy. This is accompanied by increased transcription of the cell cycle inhibitor p21 (Cip1). Lack of Aurora B does not prevent mitotic entry but results in a premature exit from prometaphase in the presence of increased p21(Cip1)-Cdk1 inactive complexes. Aurora B-null cells display reduced degradation of cyclin B1, suggesting the presence of phenomenon known as adaptation to the mitotic checkpoint, previously described in yeast. Elimination of p21(Cip1) rescues Cdk1 activity and prevents premature mitotic exit in Aurora B-deficient cells. These results suggest that Aurora B represses p21(Cip1), preventing delayed DNA replication, Cdk inhibition and premature mitotic exit. The upregulation of p21(Cip1) observed after inhibition of Aurora B may have important implications in cell cycle progression, tetraploidy, senescence or cancer therapy.
authors: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Marianna
authors: M
authors: Trakala
authors: Gonzalo
authors: G
authors: Fernández-Miranda
authors: Ignacio
authors: I
authors: Pérez de Castro
authors: Christopher
authors: C
authors: Heeschen
authors: Marcos
authors: M
authors: Malumbres
mesh_terms: D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002460:Cell Line; D056744:Cyclin B1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D059585:G1 Phase Cell Cycle Checkpoints; D007399:Interphase; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase
keywords: Aurora kinase B; G1/S progression; cancer target; mitosis; spindle assembly checkpoint