Structural centrosome abnormalities have been implicated as a potential cause of loss of cell and tissue architecture seen in cancer (i.e., anaplasia) as a result of altered centrosome function in microtubule nucleation and organization. This would result in chromosome missegregation during mitosis as a consequence of multipolar spindle formation. Previous studies of mutant mice or cell culture experiments have shown that both BRCA1 and Aurora-A are involved in the regulation of mitosis. Recently, we found that phosphorylation of BRCA1 Ser308 by Aurora-A is required for mitosis entry. The eukaryotic cell cycle is a cascade of highly complex processes that must occur with striking temporal and spatial precision. Regulatory networks called checkpoints are capable of recognizing and correcting mistakes occurring during these processes. Cells respond to DNA damage and replication blocks in two ways: They arrest the cell cycle to allow time for repair and they induce the transcription of genes that facilitate repair. In the proposed research, the infrastructure of these checkpoint circuits will be probed in mammalian cells using BRCA1 to determine how cells sense problems in mitosis. The general aim is to explore more deeply than heretofore the mechanisms of progression of mitosis regulated by BRCA1, originally uncovered by us. First, we will investigate the roles of BRCA1 phosphorylation by Aurora-A in regulation of the cyclin B1-cdk1 complex, whose activation on the centrosome is essential to enter mitosis. Second, we will study the roles of phosphorylation of BRCA1 Ser308 by Aurora-A in centrosome separation and maturation. Accumulating studies have shown that centrosome maturation in mitosis is crucial for the precise segregation of chromosomes. Biochemical and biological investigations will be formulated to understand the functional interaction of BRCA1 with Aurora-A in the centrosome cycle. Third, we will determine the mechanisms of regulation of Aurora-A by p53 and BRCA1. We plan to utilize BRCA1(-/-) mouse embryo fibroblasts (MEFs) for the proposed experiments. These studies are all aimed at a deeper understanding of both processes of oncogenic transformation and novel approaches to cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA079892-08
Application #
7408996
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Spalholz, Barbara A
Project Start
1998-12-11
Project End
2009-04-30
Budget Start
2007-05-23
Budget End
2008-04-30
Support Year
8
Fiscal Year
2007
Total Cost
$216,896
Indirect Cost
Name
Northshore University Healthsystem
Department
Type
DUNS #
069490621
City
Evanston
State
IL
Country
United States
Zip Code
60201
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So, Eui Young; Ouchi, Mutsuko; Cuesta-Sancho, Sara et al. (2015) Tumor suppression by resistant maltodextrin, Fibersol-2. Cancer Biol Ther 16:460-5
So, Eui Young; Ouchi, Toru (2014) Decreased DNA repair activity in bone marrow due to low expression of DNA damage repair proteins. Cancer Biol Ther 15:906-10
Shionome, Yoshimi; Lin, Wen-Hsing; Shiao, Hui-Yi et al. (2013) A novel aurora-A inhibitor, BPR1K0609S1, sensitizes colorectal tumor cells to 5-fluorofracil (5-FU) treatment. Int J Biol Sci 9:403-11
Shionome, Yoshimi; Yan, Li; Liu, Song et al. (2013) Integrity of p53 associated pathways determines induction of apoptosis of tumor cells resistant to Aurora-A kinase inhibitors. PLoS One 8:e55457
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Kang, Meyke Ausman; So, Eui-Young; Ouchi, Toru (2012) Deregulation of DNA damage response pathway by intercellular contact. J Biol Chem 287:16246-55
Jeon, Gye Sun; Kim, Ki Yoon; Hwang, Yu Jin et al. (2012) Deregulation of BRCA1 leads to impaired spatiotemporal dynamics of ?-H2AX and DNA damage responses in Huntington's disease. Mol Neurobiol 45:550-63
So, E Y; Ausman, M; Saeki, T et al. (2011) Phosphorylation of SMC1 by ATR is required for desferrioxamine (DFO)-induced apoptosis. Cell Death Dis 2:e128

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