title: A role for p38 in transcriptional elongation of p21 (CIP1) in response to Aurora B inhibition.
abstract: Aurora kinases play important functions in mitosis. They are overexpressed in many cancers and are targets for anticancer therapy. Inhibition of Aurora B results in cytokinesis failure and polyploidization, leading to activation of the p53 tumor suppressor and its target genes, including p21. The pathways that mediate p21 activation after Aurora B inhibition are not well understood. In this study, we identified a role for the p38 MAP kinase in activation of p21 when Aurora B is inhibited. We show that p38 is required for the acute cell cycle arrest in G 1 and to prevent endoreduplication when Aurora B is inhibited. Stabilization of p53 occurs independently of p38, and recruitment of p53 to the p21 promoter also does not require p38. Instead, enrichment of the elongating form of RNA PolII at the distal region of the p21 gene is strongly reduced when p38 is blocked, indicating that p38 acts in transcriptional elongation of p21. Thus, our results identify an unexpected role of p38 in cell cycle regulation in response to Aurora B inhibition, by promoting the transcriptional elongation of the cell cycle inhibitor p21.
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Geeta
authors.initials: G
authors.lastname: Kumari
authors.forename: Tanja
authors.initials: T
authors.lastname: Ulrich
authors.forename: Stefan
authors.initials: S
authors.lastname: Gaubatz
mesh_terms: D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D048749:Cytokinesis; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D055550:Protein Stability; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D061805:Transcription Elongation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; D001549:Benzamides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011799:Quinazolines; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C576921:AURKB protein, human; D064107:Aurora Kinase B; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Aurora B; p21; p38; p53; transcription elongation