William (Bill) R. Brinkley, Ph.D.
Distinguished Service Professor, Department of Molecular and Cellular Biology
Dean, Graduate School of Biomedical Sciences
Ph.D., Iowa State University
Postdoctoral, The University of Texas M.D. Anderson Cancer Center
Research Interests:
The Brinkley Laboratory investigates the molecular regulation of mitosis in normal and malignant human cells with the overall goal of defining the mechanism of aneuploidy, as it relates to genomic instability in cancer. For a number of years, the central focus of our laboratory has involved the mitotic apparatus, with special interest in two critical foci: the centrosomes (centrioles) located at each pole of the mitotic spindle and the centromere (kinetochore) of mitotic chromosomes that regulates chromosome movement and genome segregation. More recently, our research has focused on mitotic kinases, specifically, a family of serine/threonine kinases known as Aurora A, -B and -C. These kinases are disregulated and overexpressed in most human cancers. Our overarching hypothesis is that disregulation of Aurora kinase expression causes loss or gain of the diploid number of chromosomes, or aneuploidy. Our most recent accomplishments include Aurora kinase A associated with centrosomes and early mitotic spindles. In collaborative studies with the Subrata Sen’s laboratory at MD Anderson Cancer Center, we discovered that Aurora A plays a significant role in regulating kinetochore and chromatin-associated spindle microtubule assembly in human cells (Kataya et al, 2008). Aurora A plays a critical role in the kinetochore/chromatin associated microtubule assembly by integrating the small Ran GTPase-TPX2 pathways in this process. This was determined through silencing by siRNA and overexpression of a kinase inactive mutant. Specifically, we identified the formation of gamma-tubulin foci in the vicinity of the kinetochore-chromatin domain is needed to create microtubule nucleation sites with INCENP and TPX2-mediated activation of Aurora A as key regulator in the process. We anticipate that disregulation in the expression of any one of these intermediates would lead to chromosome instability and aneuploidy. Our study provided the first evidence for this new pathway in human mitotic cells.
The Brinkley Laboratory also continues to investigate Aurora B and Aurora C kinases (Slattery, et al. 2008, 2009). These two kinases share considerable sequence homology and overlap in their specific sites of location in mitotic cells. Interestingly, Aurora B has been highly conserved in evolution, whereas Aurora C apparently arose through gene duplication of Aurora B, and is only expressed in mammals. Aurora C is known to function in male meiosis and spermatogenesis but is overexpressed in many human tumors. Our studies have indicated that both are up-regulated in cancer cells and share phosphorylation and regulation of common mitotic substrates, Cenp-A and Borealin during mitosis. Moreover, Aurora C supports mitotic progression in competition with Aurora B in cancer cells, and is capable of performing mitotic functions previously attributed only to Aurora B (Slattery et al. 2009). Redundancy of function in mitosis could have significant importance in strategies for the design and targeting of small molecular inhibitors of the Aurora kinases in cancer chemotherapy.
Selected Publications:
Slattery, S.D. (2009). Aurora-C Kinase supports mitotic progression in competition with Aurora-B. Doctoral Dissertation, Graduate School of Biomedical Sciences, Baylor College of Medicine.
Slattery, S.D., Mancini, M., Brinkley, B.R., and Hall, R.M. (2009). Aurora-C kinase supports mitotic progression in the absence of Aurora-B. J. Cell Cycle. 8: 2984-2994. PMID: 19713763
Katayama, H., Sasai, K. M., Kloc, Brinkley, B.R. and Sen, S. (2008). Aurora kinase-A regulates kinetochore/chromatin associated microtubule assembly in human cells. Cell Cycle. 7:2691-2704. PMID: 18773538
Slattery, S.D., Moore, R.V., Brinkley, B.R. and Hall, R.M. (2008). Aurora-C and Aurora-B share phosphorylation and regulation of cenp-A and borealin during mitosis. Cell Cycle. 7:1-9. PMID: 18239465
MacCorkle, R.A, Slattery, S.D., Nash, D.R., and Brinkley, B.R. (2006). Intracellular protein binding to asbestos induces aneuploidy in human lung fibroblasts. Cell Motil Cytoskeleton. 63:646-57. PMID: 16937396
Brinkley, B.R. (2004). Elusive nucleoskeleton visualized in live cells. Cell Motil Cytoskeleton. 59:119. PMID: 15362115
Stenoien, D.L., Sen, S., Mancini, M.A., and Brinkley, B.R. (2003). Dynamic association of a tumor amplified kinase, Aurora A with the centrosome and mitotic spindle. Cell Motil. Cytoskeleton. 55:134-146. PMID: 12740874
Goepfert T M, Medina D, Brinkley BR. (2002). Centrosome amplification and overexpression of Aurora A kinase are early events in rat mammary carcinogenesis. Cancer Res. 62:4115-4122. PMID: 12124350
Brinkley, B.R. (2001). Managing the centrosome numbers game: From chaos to stability in cancer cell division. Trends in Cell Biol. 11:18-21. PMID: 11146294
Van Hooser, A.A., Ouspenski, II, Gregson, H.C., Starr, D.A., Yen, T.J., Goldberg, M.L., Yokomori, K, Earnshaw, W.C., Sullivan, K.F., and Brinkley, B.R. (2001). Specification of kinetochores-forming chromatin by the histone H3 variant CENP-A. J. Cell Sci. 114:3529-3542. PMID: 1168261
Ouspenski, ll., Cabello, O.A., and Brinkley, B.R. (2000). Chromosome condensation factor Brn1p is required for chromatid separation in mitosis. Molec. Biol. of the Cell. 11:1305-1313. PMID: 1074993
For more publications, see listing on PubMed.
Contact Information:
William (B.R.) Brinkley, Ph.D.
Graduate School of Biomedical Sciences
One Baylor Plaza, BCM215
Houston, TX 77030
(713) 798-5263
Fax: (713) 798-5762
E-mail: brinkley@bcm.edu
Updated: 11/09