Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/16477
Title: Isolation and characterization of Aurora-A Kinase Interacting Protein (AKIP), A novel negative regulator for Aurora-A Kinase
Authors: LIM SHEN KIAT
Keywords: Aurora-A Kinase, Aurora-A Kinase Interacting Protein, Antizyme, Ubiquitin-independent, Degradation, Oncogene
Issue Date: 30-Jan-2007
Source: LIM SHEN KIAT (2007-01-30). Isolation and characterization of Aurora-A Kinase Interacting Protein (AKIP), A novel negative regulator for Aurora-A Kinase. ScholarBank@NUS Repository.
Abstract: Aurora kinases have evolved as a new family of centrosome- and microtubule-associated serine/threonine kinases that regulate multiple processes in mitosis, such as centrosome duplication and maturation, chromosome condensation, bipolar spindle assembly and dynamics, cytokinesis and checkpoint control. One of its members, Aurora-A kinase is a potential oncogene. Overexpression of Aurora-A kinase causes centrosome amplification and defective chromosome segregation, leading to aneuploidy and tumorigenesis in various cancer cell types. Our objective is to identify the negative regulator(s) for mammalian Aurora-A kinase. Exploiting the lethal phenotype associated with overexpression of Aurora-A kinase in yeast, we performed a dosage suppressor screen in yeast and successfully isolated a novel negative regulator of Aurora-A kinase, named as AKIP (Aurora-A Kinase Interacting Protein). AKIP is an ubiquitously expressed nuclear protein that interacts specifically with human Aurora-A in vivo. AKIP targets Aurora-A for protein destabilization in a proteasome-dependent manner. AKIP-Aurora-A interaction is essential for the AKIP-mediated Aurora-A degradation. Aurora-A kinase normally undergoes cell cycle-dependent turnover through the Cdh1-mediated APC/C-ubiquitin-proteasome pathway. In an attempt to investigate the mechanism of AKIP-mediated Aurora-A degradation, AKIP was found to potentiate the proteasome-dependent degradation of Aurora-A by an alternative mechanism that is independent of ubiquitination. This implies Aurora-A kinase can be delivered to the proteasome for degradation via two distinct ubiquitin-dependent and ubiquitin-independent pathways. AKIP inhibits Aurora-A ubiquitination, through its interaction with the potential ubiquitination region of Aurora-A. Interestingly, AKIP-mediated Aurora-A degradation is functionally linked to a family of protein, called antizyme (AZ), which plays the proteasomal targeting role and mediates the Ub-independent degradation of some proteins. Antizyme can directly down-regulate Aurora-A protein stability, which is dependent on antizyme:Aurora-A interaction. Interestingly, defective antizyme:Aurora-A interaction or inhibition of antizyme function impairs AKIP-mediated Aurora-A degradation, implying AKIP and antizyme function on the same or parallel pathways in the ubiquitin-independent degradation of Aurora-A. AKIP indeed acts upstream of antizyme by enhancing binding of antizyme to Aurora-A, thereby targeting Aurora-A for proteasomal degradation.
URI: http://scholarbank.nus.edu.sg/handle/10635/16477
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