Abstract LB-283: Aurora B binds p53 during both interphase and mitosis, phosphorylates it and promotes its degradation

Abstract

Abstract Aurora B (AurB) is a mitotic checkpoint kinase that plays a pivotal role in the cell cycle, ensuring correct chromosome segregation and normal progression through mitosis. Tumor suppressor p53 is a genome guardian and an important negative regulator of the cell cycle. Although overexpression of AurB and loss or degradation of p53 have been described in many types of human cancers, it is not known whether AurB and p53 are coordinately regulated during the cell cycle. Recently has been shown that NIR, which is a transcriptional co-repressor of histone acetyltransferase activity, interact with and suppress p53 via interaction with AurB. Our results show that AurB directly interacts with p53 in a NIR-independent matter. To prove direct molecular interaction between AurB and p53 in whole cells, we employed the method of bimolecular fluorescent complementation (BiFC). AurB-p53 interaction occurs at the nucleus in interphase and at the centromeres in prometaphase of mitosis. We observed that AurB-p53 interaction co-localized with Survivin and CENP-A, suggesting that AurB and p53 interact at the centromeres. Our results also show that Aurora B phosphorylates p53 to accelerate p53's degradation through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis. Inhibition of Aurora B in cancer cells with wild-type p53 increased p53 protein level and expression of p53 target genes to inhibit tumor growth. Together, these results give a new insight of a novel mechanism of p53 inactivation during the cell cycle and imply that oncogenic hyperactivation or overexpression of AurB may compromise p53's tumor suppressor function. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-283. doi:1538-7445.AM2012-LB-283