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Aurora-A Kinase Regulates Breast Cancer–Associated Gene 1 Inhibition of Centrosome-Dependent Microtubule Nucleation

¹ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; ² Department of Biology, Rensselaer Polytechnic Institute, Troy, New York; ³ Marine Biological Laboratory, Woods Hole, Massachusetts; and ⁴ Department of Biomedical Informatics, The Ohio State University Medical Center, Columbus, Ohio

Requests for reprints: Jeff Parvin, Department of Biomedical Informatics, The Ohio State University, 460 West 12th Avenue, 904 Biomedical Research Tower, Columbus, OH 43210. Phone: 614-292-0523; Fax: 614-688-8675; E-mail: Jeffrey.Parvin{at}osumc.edu.

Breast cancer–associated gene 1 (BRCA1) regulates the duplication and the function of centrosomes in breast cells. We have previously shown that BRCA1 ubiquitin ligase activity directly inhibits centrosome-dependent microtubule nucleation. However, there is a paradox because centrosome microtubule nucleation potential is highest during mitosis, a phase when BRCA1 is most abundant at the centrosome. In this study, we resolve this conundrum by testing whether centrosomes from cells in M phase are regulated differently by BRCA1 when compared with other phases of the cell cycle. We observed that BRCA1-dependent inhibition of centrosome microtubule nucleation was high in S phase but was significantly lower during M phase. The cell cycle–specific effects of BRCA1 on centrosome-dependent microtubule nucleation were detected in living cells and in cell-free experiments using centrosomes purified from cells at specific stages of the cell cycle. We show that Aurora-A kinase modulates the BRCA1 inhibition of centrosome function by decreasing the E3 ubiquitin ligase activity of BRCA1. In addition, dephosphorylation of BRCA1 by protein phosphatase 1 enhances the E3 ubiquitin ligase activity of BRCA1. These observations reveal that the inhibition of centrosome microtubule nucleation potential by the BRCA1 E3 ubiquitin ligase is controlled by Aurora-A kinase and protein phosphatase 1–mediated phosphoregulation through the different phases of the cell cycle. [Cancer Res 2007;67(23):11186–94]

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