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Gary J. Gorbsky, Ph.D.

Gary J. Gorbsky, Ph.D.

Gary J. Gorbsky, Ph.D.

Member and Program Chair

W.H. and Betty Phelps Chair in Developmental Biology

Adjunct Professor, Department of Cell Biology, University of Oklahoma Health Sciences Center

The nucleus of normal human cells contains our genetic blueprint which is organized into 23 pairs of chromosomes, or a total of 46 chromosomes that each contain between one and two thousand genes. Every time a cell divides, each chromosome is carefully replicated and then distributed such that each of the new cells gets a complete and accurate set of chromosomes. Chromosome instability, or a defect in the movement or distribution of chromosomes during cell division, is a major cause of congenital birth defects and major factor in the development of cancer.

Research in my laboratory focuses on the basic mechanisms of how chromosomes assemble and move during cell division, in both normal cells and cancer cells. We are specifically interested in a system in cells that makes sure that the copies of the 46 chromosomes are distributed equally to each of the dividing cells. This checkpoint system works at a specific phase in cell division when the duplicated chromosomes have moved to the middle of the cell along track-like structures called spindle microtubules. The results of research in my laboratory have made major contributions to understanding the how this checkpoint system works. Our studies have discovered that the checkpoint provides a signal to the cell to prevent the chromosomes from segregating until it is sure that the chromosomes are all in the right place. Only when all the chromosomes are correctly attached to the spindle microtubules and aligned properly in the cell is the checkpoint signal turned off and the chromosomes allowed to separate. Thus, a single unattached chromosome can block the segregation of all the others. The way in which the checkpoint signal is produced and turned on and off properly is a consequence of a remarkably complex set of protein interactions. By using advanced techniques of fluorescence microscopy, we are able to study in real-time the interactions of the proteins involved in checkpoint pathway by actually visualizing them in living cells. In addition, we use modern approaches in molecular biology and biochemistry to study the functional interactions of these proteins.

In cancer cells, the checkpoint system is often faulty, leading to the generation of cells with too many or too few chromosomes. An abnormal number of chromosomes causes the cell to have the wrong proportion of regular genes along with losing a number of normal gene functions, and can therefore produce abnormal cells with malignant characteristics. So although a faulty checkpoint system can have disastrous consequences, the defects may also be used as a way to distinguish cancer cells from normal cells. We are investigating whether the defective components of cell cycle checkpoints can provide specific targets for drugs that could then be used to destroy the cancer cells. In additional experiments aimed at improving the efficiency of checkpoint anti-cancer agents, we are using high-throughput drug screening assays to search through libraries made up of thousands of small chemical compounds. We presently have identified lead compounds that precisely target components of the checkpoint pathway and drugs based on our findings may one day be used in anti-cancer therapy.

Overall, our research goals are to understand how the progression through cell division is regulated, how this regulation becomes defective in cancer cells, and how we can take advantage of these defects to develop novel approaches for the treatment of cancer.

Education
B.S., College of William and Mary, Williamsburg VA, 1976
M.S., Princeton University, Princeton NJ, 1978
Ph.D., Princeton University, Princeton NJ, 1982

Joined OMRF Scientific Staff in 2003.

Chromosome instability, the mis-segregation of chromosomes during meiosis and mitosis, is a major cause of congenital birth defects and an important contributing element in cancer malignancy. We have characterized some of the components of the cell cycle checkpoints that regulate the timing of chromosome segregation to ensure the genetic material is equally distributed to the newly formed cells during division. Our laboratory uses a combination of molecular biology and advanced imaging of living cells by microscopy to study the mechanisms of chromosome movement and how these movements influence checkpoint signaling.

The kinetochore is an organelle that forms during meiosis and mitosis at the centromeric chromatin and serves to move chromosomes and to integrate cell cycle progression. Previously, our laboratory showed that translocation of the kinetochores along microtubules is the prime mediator of chromosome movement in mitosis. We later discovered that individual kinetochores within a mitotic cell were biochemically distinct and developed the model of kinetochores as the sites where cell cycle progression through mitosis is regulated.

Currently, we are addressing the mechanochemistry of the motors that move chromosomes in mitosis and how these mechanical forces act to modulate kinase and phosphatase activities at the kinetochores of mitotic chromosomes. We have identified functions for several of the biochemical components of kinetochores including the Ndc80 protein complex and the Aurora B kinase. Recently, we discovered that the activity of another regulator, polo-like kinase-1, at mitotic kinetochores is regulated by the mechanical tension imparted by the attachment of the spindle microtubules.

In other studies we are investigating whether the defective cell cycle checkpoints of cancer cells may provide a target for the development of therapeutics that are specifically effective against tumors. Overall, we seek to understand how progression through cell division is regulated, how this regulation becomes defective in cancer cells and how these defects might be exploited to develop novel approaches in cancer therapy.

Recent Publications

Sivakumar S, Daum JR, Gorbsky GJ. Live-Cell Fluorescence Imaging for Phenotypic Analysis of Mitosis. Methods Mol Biol 1170:549-562, 2014. [Abstract]

Sivakumar S, Daum JR, Tipton AR, Rankin S, Gorbsky GJ. The Spindle and kinetochore-associated (Ska) complex enhances binding of the Anaphase-Promoting Complex/Cyclosome (APC/C) to chromosomes and promotes mitotic exit. Mol Biol Cell 25:594-605, 2014. [Abstract]

Gorbsky GJ. Cohesion fatigue. Curr Biol 23:R986-R988, 2013. [Abstract]

Selected Publications
Daum JR, Potapova TA, Sivakumar S, Daniel JJ, Flynn JN, Rankin S, Gorbsky GJ. Cohesion fatigue induces chromatid separation in cells delayed at metaphase. Curr Biol 21:1018-1024, 2011. [Abstract]

Potapova TA, Sivakumar S, Flynn JN, Li R, Gorbsky GJ. Mitotic progression becomes irreversible in prometaphase and collapses when Wee1 and Cdc25 are inhibited. Mol Biol Cell 22:1191-1206, 2011. [Abstract]

Wang F, Dai J, Daum JR, Niedzialkowska E, Banerjee B, Stukenberg PT, Gorbsky GJ, Higgins JM.  Histone H3 Thr-3 phosphorylation by Haspin positions Aurora B at centromeres in mitosis. Science 330:231-235, 2010. [Abstract]

Daum JR, Wren JD, Daniel JJ, Sivakumar S, McAvoy JN, Potapova TA, Gorbsky GJ.  Ska3 is required for spindle checkpoint silencing and the maintenance of chromosome cohesion in mitosis. Curr.Biol. 19:1467-1472, 2009. [Abstract]

Demoe JH, Santaguida S, Daum JR, Musacchio A, Gorbsky GJ.  A high throughput, whole cell screen for small molecule inhibitors of the mitotic spindle checkpoint identifies OM137, a novel Aurora kinase inhibitor. Cancer Res. 69:1509-1516, 2009. [Abstract]

Potapova TA, Daum JR, Pittman BD, Hudson JR, Jones TN, Satinover DL, Stukenberg PT, Gorbsky GJ. The reversibility of mitotic exit in vertebrate cells. Nature 440:954-958, 2006. [Abstract]

Cell Cycle and Cancer Biology Research Program, MS 48
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104

Phone: (405) 271-8168
Fax: (405) 271-7312
gary-gorbsky@omrf.org
http://cccb.omrf.org/gorbskylab/

Our Lab webpage: http://cccb.omrf.org/gorbskylab/

Carlie Milfort
Graduate Student

Sushama Sivakumar
Graduate Student

John Daum
Laboratory Manager

Gene Chao
Network & Computer Systems Administrator

Evan Fields
Research Technician

Cheri Rutledge
Executive Assistant

Gerry McElroy
Laboratory Assistant