This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sankaran, S. Articles by Parvin, J. D. Search for Related Content PubMed PubMed Citation Articles by Sankaran, S. Articles by Parvin, J. D.

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]

This article has been cited by other articles:

				P. Kalab and R. Heald The RanGTP gradient - a GPS for the mitotic spindle J. Cell Sci., May 15, 2008; 121(10): 1577 - 1586. [Abstract] [Full Text] [PDF]