AURORA-A, A POTENTIAL TARGET IN PANCREATIC CANCER AND ITS STRUCTURAL ROLE IN LOCALIZATION TO THE CENTROSOMES
Committee ChairBosco, Giovanni
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PublisherThe University of Arizona.
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AbstractAurora-A kinase is overexpressed in many human cancers and leads to centrosome amplification resulting in multipolar spindles, chromosome segregation defects and aneuploidy. Aurora-A belongs to a family of serine/threonine mitotic kinases involved in centrosome separation, duplication and maturation as well as in bipolar spindle assembly. In this work, we demonstrate that Aurora-A is both amplified and overexpressed in human pancreatic cancer cell lines, with a 2-5 fold increase in gene copy number and a 3-4 fold increase in protein levels compared to controls. Aurora-A is also amplified and overexpressed in pancreatic cancers taken directly from patients. An immunohistochemistry of tissues taken directly from patients demonstrated an overexpression of Aurora-A in 26 of 28 pancreatic cancers compared to 0 of 18 normal pancreas samples. Antisense nucleotides specifically targeted at Aurora-A arrest the cell cycle in pancreatic cancer cells, indicating the potential of Aurora-A as a therapeutic target in pancreatic cancer. To understand the role of Aurora-A at the centrosome, we investigated the mechanism of how Aurora-A is targeted to the centrosome. We used deletion fragment analysis of Aurora-A to identify a specific region that is required to localize to the centrosome. We also show that subcellular localization of Aurora-A is independent of its intrinisic kinase activity and its phosphorylation states. These results show that Aurora-A is targeted to the centrosome by a mechanism that does not require its kinase activity and phosphorylation of T288 and T287. Furthermore, the region containing the catalytic domain, 131-333, is sufficient to localize Aurora-A to the centrosome.
Degree ProgramMolecular & Cellular Biology