Antizyme1 mediates AURKAIP1-dependent degradation of Aurora-A.
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.
Lim
S K
SK
Laboratory of Gene Structure and Expression, Division of Molecular and Cellular Research, National Cancer Centre, Singapore, Singapore.
Gopalan
G
G
D019943:Amino Acid Substitution; D000818:Animals; D064127:Aurora Kinases; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism* / Q000494:pharmacology*; D012156:Reticulocytes; D014162:Transfection; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D025801:Ubiquitin; C103265:aryl hydrocarbon receptor-interacting protein; C031017:ornithine decarboxylase antizyme; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex