Abstract
Overexpression of Aurora-A oncogene has been shown to induce genomic instability and tumorigenesis. Cellular levels of Aurora-A are regulated by multiple mechanisms including the proteasome-dependent degradation of Aurora-A protein. Cell-cycle-dependent turnover of Aurora-A protein is mediated by cdh1 through ubiquitin (Ub)- and proteasome-dependent pathway. However, Aurora-A kinase interacting protein 1 (AURKAIP1), a negative regulator of Aurora-A, also promotes proteasome-dependent Aurora-A degradation through an Ub-independent mechanism. In an attempt to understand how AURKAIP1 promotes Aurora-A degradation through Ub-independent pathway, we demonstrate here that antizyme1 (Az1), a well-studied mediator of Ub-independent protein degradation pathway, regulates Aurora-A protein stability. We show that ectopic or polyamine-induced expression of Az1 can lower the steady-state levels of Aurora-A. The effect of Az1 on Aurora-A turnover was shown to be proteasome-dependent, but Ub-independent. Az1 interacts with Aurora-A in vivo and the interaction between Aurora-A and Az1 is essential for the Az1-mediated Aurora-A degradation. Furthermore, we observed that AURKAIP1 could not promote degradation of Aurora-A mutant, which is defective in Az1 interaction. Coexpression of the Az inhibitor (AzI), which downregulates Az1 functions, also abrogated AURKAIP1-mediated degradation of Aurora-A. We further demonstrated that AURKAIP1, Az1 and Aurora-A could exist as a ternary complex and AURKAIP1 enhances the interaction between Az1 and Aurora-A. We propose that AURKAIP1 might function upstream of the Az1 by enhancing the binding affinity of Az1 to Aurora-A to promote recognition, targeting to proteasome and subsequent degradation.
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Acknowledgements
We thank Dr Ger J Strous and Dr Issacs for providing us the ts20-CHO and AT2.1 rat prostate carcinoma cell lines, respectively. We also thank Dr Geisen, Dr Coffino and Dr Prochownik for the p27kip1, mouse ODC and cyclinB1 expression plasmids, respectively. We acknowledge the generosity of Dr John Mitchell for the anti-antizyme antibody. This work was supported by the National Medical Research Council of Singapore in the form of a research grant (NMRC/0815/2003) to GG and as Institutional Block Grant to National Cancer Centre, Singapore.
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Lim, S., Gopalan, G. Antizyme1 mediates AURKAIP1-dependent degradation of Aurora-A. Oncogene 26, 6593–6603 (2007). https://doi.org/10.1038/sj.onc.1210482
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DOI: https://doi.org/10.1038/sj.onc.1210482
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