Aurora-A/BTAK/STK15 Oncoprotein in Mitotic Spindle Assembly and Checkpoint Respon

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DESCRIPTION (provided by applicant): Aurora-A/BTAK/STK15 is a critical regulator of mitotic chromosome segregation and a putative oncoprotein capable of inducing chromosomal instability and oncogenic transformation when ectopically over expressed in mammalian cells in vitro and in vivo. A significant correlation has been reported between elevated expression of the protein and chromosomal instability in many different types of human cancers and several clinical trials of small molecule Aurora kinase inhibitors for cancer therapy are currently underway. Our recent work on molecular interactions of Aurora-A in human cells and the development of a knockout mouse model have provided compelling evidence in favor of novel functional roles of Aurora-A in mitotic spindle assembly and checkpoint as well as cell survival pathways. The results have revealed that Aurora-A is the key regulator of both kinetochore/chromatin and centrosome associated microtubule formation processes contributing to bipolar spindle assembly and that loss of Aurora-A function leads to cell death following mitotic disarray. This application proposes to investigate the functional significance of novel Aurora-A protein interactions, recently detected in our laboratory, in the regulation of mitotic spindle assembly, mitotic checkpoint and cell survival/cell death response pathways in human cells. Additionally, expression patterns of these Aurora-A interacting proteins will be correlated with response to therapy and overall survival in human breast cancer patients. The study will have the following specific aims: 1. Investigate the role of Aurora-A in kinetochore/chromatin associated microtubule assembly in reference to its functional interactions with INCENP and the chromosome passenger complex proteins. 2. Investigate the role of novel centrosome/spindle pole associated Aurora-A interactions with Translin, EF11 and Hsp90 in spindle assembly. 3. Investigate the role of Aurora-A-CENP-E interaction on spindle assembly checkpoint pathway. 4. Investigate the role of two novel Aurora-A interacting proteins, the Chk2 kinase and the mitochondrial membrane protein MTP18 in the survival of cells and in the activation of mitotic cell death response in the absence or presence of spindle damaging drugs. 5. Investigate the expression status of the novel Aurora-A interacting proteins in human breast cancer tissue specimens with in situ and invasive carcinoma. The results are expected to provide a comprehensive picture of Aurora-A regulated pathways in mitotic progression including chromosome alignment, segregation, checkpoint and cell survival/cell death response in human cells as well as evaluate the significance of Aurora-A interacting proteins in response to therapy and over all survival of human breast cancer patients. PUBLIC HEALTH RELEVANCE: This project proposes to: 1. Investigate the significance of novel kinetochore and centrosome associated Aurora-A functional interactions in kinetochore and centrosome associated mitotic spindle assembly. 2. Investigate the significance of novel Aurora-A functional interactions with Cenp- E, Chk2 and MTP18 in checkpoint and cell survival/cell death response in human cells exposed to spindle damaging agents and correlate the expression profiles of these proteins with response to therapy in human breast cancer patients.