AURORA-A, A POTENTIAL TARGET IN PANCREATIC CANCER AND ITS STRUCTURAL ROLE IN LOCALIZATION TO THE CENTROSOMES

Persistent Link:
http://hdl.handle.net/10150/194492
Title:
AURORA-A, A POTENTIAL TARGET IN PANCREATIC CANCER AND ITS STRUCTURAL ROLE IN LOCALIZATION TO THE CENTROSOMES
Author:
Rojanala, Sangeeta
Issue Date:
2005
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Aurora-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.
Type:
text; Electronic Dissertation
Keywords:
centrosome; kinase; phosphorylation; aurora-2; aurora-A; pancreactic cancer
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Molecular & Cellular Biology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Bosco, Giovanni
Committee Chair:
Bosco, Giovanni

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleAURORA-A, A POTENTIAL TARGET IN PANCREATIC CANCER AND ITS STRUCTURAL ROLE IN LOCALIZATION TO THE CENTROSOMESen_US
dc.creatorRojanala, Sangeetaen_US
dc.contributor.authorRojanala, Sangeetaen_US
dc.date.issued2005en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.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.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectcentrosomeen_US
dc.subjectkinaseen_US
dc.subjectphosphorylationen_US
dc.subjectaurora-2en_US
dc.subjectaurora-Aen_US
dc.subjectpancreactic canceren_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineMolecular & Cellular Biologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorBosco, Giovannien_US
dc.contributor.chairBosco, Giovannien_US
dc.contributor.committeememberSchroeder, Joyceen_US
dc.contributor.committeememberNagle, Rayen_US
dc.contributor.committeememberParker, Royen_US
dc.identifier.proquest1121en_US
dc.identifier.oclc659747427en_US
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