Aurora B kinase phosphorylates and instigates degradation of p53

Abstract

Aurora B is a mitotic checkpoint kinase that plays a pivotal role in the cell cycle, ensuring correct chromosome segregation and normal progression through mitosis. Aurora B is overexpressed in many types of human cancers, which has made it an attractive target for cancer therapies. Tumor suppressor p53 is a genome guardian and important negative regulator of the cell cycle. Whether Aurora B and p53 are coordinately regulated during the cell cycle is not known. We report that Aurora B directly interacts with p53 at different subcellular localizations and during different phases of the cell cycle (for instance, at the nucleus in interphase and the centromeres in prometaphase of mitosis). We show that Aurora B phosphorylates p53 at S183, T211, and S215 to accelerate the degradation of p53 through the polyubiquitination–proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and PUMA). Pharmacologic inhibition of Aurora B in cancer cells with WT p53 increased p53 protein level and expression of p53 target genes to inhibit tumor growth. Together, these results define a mechanism of p53 inactivation during the cell cycle and imply that oncogenic hyperactivation or overexpression of Aurora B may compromise the tumor suppressor function of p53. We have elucidated the antineoplastic mechanism for Aurora B kinase inhibitors in cancer cells with WT p53.

FBXW7 is involved in Aurora B degradation

“…Clearly, the FBXW7-Aurora B link will be an important molecular target for rational cancer therapy. Since FBXW7 expression p53 and subsequently enhance MDM2-mediated p53 degradation 21,40 or suppress p53 transcriptional activity. 41 Our study of FBXW7-mediated Aurora B degradation indicates that a feedback loop exists to maintain the equilibrium between Aurora B, p53 and FBXW7 (Fig.…”

“…We previously showed that Aurora B is a kinase that can negatively regulate p53 stability. 21 Because the stability of both p53 and Aurora B is regulated through ubiquitination, ubiquitin-mediated stabilization could play an important role for coordinating this inverse relationship. We examined whether FBXW7, a p53 target gene product and an E3 ubiquitin ligase component, has a biological impact on Aurora B.…”

“…Flag-Aurora B, GFP-Aurora B, Flag-FBXW7, DNFBWX7, DNFBWX7R mutants and His-p53 were previously described. 21,23,[43][44][45] Aurora B shRNA was previously described.…”

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

“…19 Aurora B kinase phosphorylates p53 at S183, T211, and S215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis. 7 Inhibition of Aurora B kinase contributes to the aneuploidy, loss of mitochondrial membrane potential, activation of caspase-9 followed by activation of caspase-3. 20,21 In a preclinical study, the inhibition of Aurora B kinase via AZD1152 was found to inhibit the growth of colon, lung and hematologic tumor xenografts in immunodeficient mice.…”

“…The over-expressions of Aurora A and B kinases have been observed in many types of human cancer, including cervical cancer, ovarian cancer, breast cancer, colorectal cancer, and gastric cancer. [5][6][7][8] Aurora A kinase controls centrosome maturation, mitotic spindle formation, chromosomes segregation and the process of cytokinesis in mammalian cells. [9][10][11] Aurora A kinase affects DNA repair and thus controls the radio-and chemosensitivities of cancer cells.…”