Why mutations in the BRCA1 gene result in breast and ovarian cancer is unknown. Recent data from this laboratory suggest that the ubiquitination activity of the BRCA1 tumor suppressor regulates the duplication and function of centrosomes specifically in mammary epithelial cells in tissue culture. Using a transient assay to inhibit BRCA1 function, we have not observed centrosome amplification in cell lines derived from non- breast tissue. Centrosome amplification has been observed in the earliest and most aggressive breast cancer lesions, and it is likely that this function of BRCA1 is critical in the etiology of these tumors. Our data has revealed a new biological pathway, which controls centrosome number and function and which depends on the function of BRCA1 in breast cells. This project will dissect the BRCA1 function via three aims. 1.) Polypeptide targets of BRCA1 ubiquitination will be identified from centrosomes purified from breast cell lines. Proteins modified by the BRCA1-dependent ubiquitination activity will be assayed for effects on centrosome duplication. 2.) The effects of BRCA1-dependent ubiquitination on centrosome microtubule nucleation function will be assayed in vitro and in vivo, and the proteins and ubiquitinated substrates identified in aim 1 will also be tested for modulating the function of BRCA1 on this organelle. 3.) We will identify the factors in non-breast cells which render the BRCA1 ubiquitination activity redundant, and test whether the newly identified factor plus BRCA1 regulate centrosome amplification in these cell types. This project will identify the mechanism by which BRCA1 regulates centrosome duplication and centrosome function in breast cells. One of the earliest changes in the cells in an incipient breast cancer is a problem with the cellular machine that segregates the DNA when the breast cell divides. Research in this laboratory has found that the function of this machine, called a centrosome, is controlled in breast cells by the BRCA1 protein. This project will dissect the workings of the centrosome and determine how BRCA1 controls its function in normal cells, and we will learn how this process is changed when BRCA1 function is lost by mutation as happens in breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Spalholz, Barbara A
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Ohio State University
Schools of Medicine
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Kais, Z; Chiba, N; Ishioka, C et al. (2012) Functional differences among BRCA1 missense mutations in the control of centrosome duplication. Oncogene 31:799-804
Liu, Hui-wen; Zhang, Jie; Heine, George F et al. (2012) Chromatin modification by SUMO-1 stimulates the promoters of translation machinery genes. Nucleic Acids Res 40:10172-86
Arora, Mansi; Zhang, Jie; Heine, George F et al. (2012) Promoters active in interphase are bookmarked during mitosis by ubiquitination. Nucleic Acids Res 40:10187-202
Kais, Zeina; Barsky, Sanford H; Mathsyaraja, Haritha et al. (2011) KIAA0101 interacts with BRCA1 and regulates centrosome number. Mol Cancer Res 9:1091-9
Hammond-Martel, Ian; Pak, Helen; Yu, Helen et al. (2010) PI 3 kinase related kinases-independent proteolysis of BRCA1 regulates Rad51 recruitment during genotoxic stress in human cells. PLoS One 5:e14027
Johnson, Neil; Cai, Dongpo; Kennedy, Richard D et al. (2009) Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage. Mol Cell 35:327-39
Kais, Zeina; Parvin, Jeffrey D (2008) Regulation of centrosomes by the BRCA1-dependent ubiquitin ligase. Cancer Biol Ther 7:1540-3
Sankaran, Satish; Crone, Donna E; Palazzo, Robert E et al. (2007) Aurora-A kinase regulates breast cancer associated gene 1 inhibition of centrosome-dependent microtubule nucleation. Cancer Res 67:11186-94
Sankaran, Satish; Crone, Donna E; Palazzo, Robert E et al. (2007) BRCA1 regulates gamma-tubulin binding to centrosomes. Cancer Biol Ther 6:1853-7
Sankaran, Satish; Parvin, Jeffrey D (2006) Centrosome function in normal and tumor cells. J Cell Biochem 99:1240-50

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