Please use this identifier to cite or link to this item:
Title: Isolation and characterization of Aurora-A Kinase Interacting Protein (AKIP), A novel negative regulator for Aurora-A Kinase
Keywords: Aurora-A Kinase, Aurora-A Kinase Interacting Protein, Antizyme, Ubiquitin-independent, Degradation, Oncogene
Issue Date: 30-Jan-2007
Citation: 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.
Appears in Collections:Ph.D Theses (Open)

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
PhD Thesis-Shen Kiat.pdf7.58 MBAdobe PDF



Page view(s)

checked on Nov 17, 2018


checked on Nov 17, 2018

Google ScholarTM


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.