Induction of p21CIP1 protein and cell cycle arrest after inhibition of Aurora B kinase is attributed to aneuploidy and reactive oxygen species.
Cell cycle progression requires a series of highly coordinated events that ultimately lead to faithful segregation of chromosomes. Aurora B is an essential mitotic kinase, which is involved in regulation of microtubule-kinetochore attachments and cytokinesis. Inhibition of Aurora B results in stabilization of p53 and induction of p53-target genes such as p21 to inhibit proliferation. We have previously demonstrated that induction of p21 by p53 after inhibition of Aurora B is dependent on the p38 MAPK, which promotes transcriptional elongation of p21 by RNA Pol II. In this study, we show that a subset of p53-target genes are induced in a p38-dependent manner upon inhibition of Aurora B. We also demonstrate that inhibition of Aurora B results in down-regulation of E2F-mediated transcription and that the cell cycle arrest after Aurora B inhibition depends on p53 and pRB tumor suppressor pathways. In addition, we report that activation of p21 after inhibition of Aurora B is correlated with increased chromosome missegregation and aneuploidy but not with binucleation or tetraploidy. We provide evidence that p21 is activated in aneuploid cells by reactive oxygen species (ROS) and p38 MAPK. Finally, we demonstrate that certain drugs that act on aneuploid cells synergize with inhibitors of Aurora B to inhibit colony formation and oncogenic transformation. These findings provide an important link between aneuploidy and the stress pathways activated by Aurora B inhibition and also support the use of Aurora B inhibitors in combination therapy for treatment of cancer.
From the Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, 97080 Wuerzburg, Germany and.
Geeta
G
Kumari
From the Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, 97080 Wuerzburg, Germany and.
Tanja
T
Ulrich
the Institute for Molecular Biology and Tumor Research (IMT), University of Marburg, Emil-Mannkopffstrasse 2, 35033 Marburg, Germany.
Michael
M
Krause
the Institute for Molecular Biology and Tumor Research (IMT), University of Marburg, Emil-Mannkopffstrasse 2, 35033 Marburg, Germany.
Florian
F
Finkernagel
From the Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, 97080 Wuerzburg, Germany and stefan.gaubatz@biozentrum.uni-wuerzburg.de.
Stefan
S
Gaubatz
D000782:Aneuploidy; D064107:Aurora Kinase B / Q000187:drug effects*; D002453:Cell Cycle; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D005434:Flow Cytometry; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D064107:Aurora Kinase B; D048051:p38 Mitogen-Activated Protein Kinases
Aneuploidy; Aurora B; Cell Cycle; Reactive Oxygen Species (ROS); Retinoblastoma Protein (pRb, RB); p21; p38 MAPK; p53