A role for p38 in transcriptional elongation of p21^CIP1in 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.

p38 mitogen-activated protein kinase inhibits USP22 transcription in HeLa cells

“…One study showed that p38 MAPK stabilizes p21 mRNA (22). Another study reported that p38 MAPK can enhance p21 expression by promoting the transcriptional elongation (23). USP22 acts upstream of p21 and represses p21 expression (4) and the present results indicate that expression of the p38 MAPK promoter p21 may take place partially through USP22 downregulation.…”

Induction of p21CIP1 Protein and Cell Cycle Arrest after Inhibition of Aurora B Kinase Is Attributed to Aneuploidy and Reactive Oxygen Species

“…This allows for rapid induction of p21 after p53 activation. We have recently shown that induction of p21 after inhibition of Aurora B depends on p38 MAPK signaling (10). We found that p38 is not required for stabilization of p53 or for binding of p53 to the p21 promoter but that it instead promotes transcriptional elongation of p21 by RNA Pol II in response to Aurora B inhibition.…”

“…Aurora B Are Dependent on p38 Signaling-We and others have recently shown that inhibition of the mitotic kinase Aurora B results in induction of the CDK inhibitor p21 (8,10,(21)(22)(23)(24)(25). Experiments with pharmacological inhibitors, isogenic cell lines, and specific siRNAs demonstrated that induction of p21 in response to Aurora B inhibition requires p53 as well as the MAPK p38 (10).…”

“…After failure of cytokinesis, cells arrest as 4N cells in G1 phase of the subsequent cell cycle. The cyclin-dependent kinase inhibitor p21, a p53-target gene, plays a critical role in mediating growth arrest upon inhibition of Aurora B (7,8,10). The expression of p21 is primarily controlled at the transcriptional level.…”

The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

“…[34][35][36] In recent studies, the activation of p38 MAPK has been suggested to be induced by Aurora B kinase inhibition. 37,38 However, the role of p38 MAPK in VX680-induced effects remains unclear.…”