This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator. A major challenge facing cancer researchers is the development of technologies that significantly increase cure rates. This can only be achieved when we more fully understand cancer pathophysiology so that new anticancer agents can be discovered and better integration of pharmacogenomics can be developed. Aurora-A regulates multiple processes during the cell cycle and mitosis, including centrosome maturation, mitosis entry, nuclear envelope breakdown, bi-polar spindle formation and orientation, cytokinesis and cell polarity for asymmetric cell division. Thus, it is not surprising that Aurora-A is found to be amplified in a plethora of cancers particularly leukemia and those of epithelial origin, namely, breast, colon, bladder, ovarian, and pancreatic. Aurora-A may promote tumor initiation, progression and metastasis, and its malfunction may lead to cell transformation and cancer in a number of different ways. By interacting with distinct Aurora-A interacting proteins (AurAIPs), Aurora-A could assemble into different signaling modules, and its misregulation could transform cells into different cancer types that would differentially respond to Aurora-A inhibitors. Thus, there is an urgent need to understand how these pathways are activated and the result of their activation in order to understand their role in neoplasia and develop strategies for treatment. The long-term goal of our lab is to develop an effective diagnosis and therapeutic approach for cancer treatment utilizing the Aurora A kinase (Aurora-A) pathways. We proposed to use our understanding of how Aurora-A is activated by Aurora-A interacting proteins (AurAIPs) to develop translational applications, which will enhance the potential for population-targeted therapy. Our lab has characterized one of the several oncogenic AurAIPs, TPX2 as the first activator identified for Aurora-A. We have identified HURP as another AurAIP that activates Aurora-A in Xenopus egg extract. We will utilize novel assays developed by our lab to understand how Aurora-A is regulated by these structurally-unrelated AurAIPs in the various steps of mitosis. Understanding how each Aurora-A activation pathway links to tumorigenesis will facilitate rapid diagnosis and ensure appropriate population targeting of the Aurora-A pathway for anti-cancer therapy. A.1. Examine how AurAIPs interaction with Aurora-A is regulated Our published studies have characterized how one AurAIP, TPX2, spatiotemporally interacts with Aurora-A. Briefly, active TPX2 interacts with Aurora-A and targets Aurora-A to the spindle. Binding of Importin / to TPX2 prevents TPX2 from interacting with Aurora-A. Ran is a spatial regulator of spindle assembly that can release TPX2 from the inhibitory binding of Importin / . In this aim, we will characterize how the interaction of other AurAIPs with Aurora-A is regulated in cell cycle progression.A.2. Examine whether the association of Aurora-A with its substrates is regulated by AurAIPs To function as molecular scaffolds, AurAIPs should be able to increase the efficiency of signaling by locally concentrating proteins and positioning Aurora-A in close proximity to its substrates. We will investigate whether AurAIPs also regulate pathway-specificity of Aurora-A by selectively bringing specific substrate(s) to Aurora-A.A.3. Examine how AurAIPs regulate Aurora-A function Although much effort has been devoted to studying the functions of AurAIPs individually, very few studies have been directed at understanding how the actions of these AurAIPs are coupled with one another and whether this coupling is important in the regulation of Aurora-A function. Studies addressing this question have been hampered by a lack of assays allowing one to address the complex issue of cross regulation. We plan to use a number of in vitro and in vivo assays to study how four AurAIPs might coordinately regulate Aurora-A function.
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