William (Bill) R. Brinkley, Ph.D
Distinguished Service Professor
Department of Molecular and Cellular Biology
Senior Vice President,Graduate Sciences
Dean, Graduate School of Biomedical Sciences
- Ph.D., Iowa State University
- Postdoc, The University of Texas MD Anderson Cancer Center
The faithful and correct partitioning of the replicated genome to each daughter nucleus of dividing cells is the central theme of mitosis. Errors in mitosis lead to the gain or loss of chromosomes from a diploid set, a condition known as aneuploidy, one form of genomic instability common to most human tumors. We seek to understand the molecular basis of errors and defects in the nucleus and mitotic apparatus (MA) that cause aneuploidy. Our research utilizes molecular biology and genetic approaches combined with digital image analysis at the light and electron microscopy levels to analyze normal and defective features of chromosome condensation, attachment and alignment on the spindle and movements during mitosis in normal and neoplastic cells.
Our experiments are focused on two important components of the MA, the centromere/kinetochore on chromosomes and the centrosomes located at each spindle pole. These two structural domains, also known as microtubule organizing centers (MTOCs), are physically connected by spindle microtubules and are critical for the proper alignment of chromosomes at the metaphase plate and their segregation and movement to the spindle poles at anaphase. Studies of the centromere are aimed at understanding DNA-protein interactions involving both constitutive and facultative centromere proteins (CENPs). One major objective is to determine the role CENPs play in establishing a functional centromere and facilitating the assembly of kinetochores, specialized plate-like structures that form along the centromeres, to which spindle microtubules are attached. We have recently discovered and are currently characterizing a 95 kD DNA-binding protein, called CENP-G, that was detected using rare human autoantibodies. CENP-G is thought to play an essential role in kinetochore assembly and we seek to understand its role in kinetochore function. Further studies of this protein in other CENPs may provide important insight as to how errors in chromosome movement and partitioning into daughter nuclei lead to genomic instability and cancer.
Experiments are also underway to identify proteins in the centrosome and the pericentrosomal region that are essential for the replication and function of this essential cytoplasmic domain. In normal diploid cells, centrosomes replicate once and only once in each cell cycle, producing a pair of centrosomes that split apart to form the two spindle poles that function in spindle assembly and chromosome partitioning. When three or more centrosomes arise by error, a multipolar spindle forms in mitosis causing mal-distribution of chromosomes. Usually, such errors are catastrophic, leading to "mitotic chaos" and cell death (apoptosis) but occasionally cells with aneuploid genomes survive and grow into malignant tumors. We are characterizing a new gene, STK15/BTAK and investigating related genes thought to be responsible for centrosome amplification common in breast cancer cells as well as those of other human malignancies.
In recent experiments carried out with my co-worker, Dr. Thea Goepfert, we have embarked on a study of precancerous cells (potential "cancer stem cells."): that we have identified during tumorigenesis in rat mammary epithelium following treatment with the carcinogen MNU.
- Stenoien DL, Sen S, Mancini MA, Brinkley BR. (2003) Dynamic association of a tumor amplified kinase, Aurora A with the centrosome and mitotic spindle. Cell Motil. Cytoskeleton. 55:134-146
- 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.
- Brinkley BR. (2001) Managing the centrosome numbers game: From chaos to stability in cancer cell division. Trends in Cell Biol. 11:18-21.
- Van Hooser AA, et al. (2001) Specification of kinetochores-forming chromatin by the histone H3 variant CENP-A. J. Cell Sci. 114:3529-3542.
- Ouspenski II, Cabello OA, Brinkley BR. (2000) Chromosome condensation factor Brn1p is required for chromatid separation in mitosis. Molec. Biol. of the Cell 11:1305-1313.
- Ouspenski II, Brinkley BR. (1993) Centromeric DNA cloned from functional kinetochore fragments in mitotic cells with unreplicated genomes. J. Cell Sci. 105:359-367.
- Zinkowski RP, Meyne J, Brinkley BR. (1991) The centromere- kinetochore complex: A repeat subunit model. J. Cell Biol. 113:1091-1110.