The long term objectives of this project are to understand the mechanisms that regulate chromosome movement and cell cycle control in mitosis. Balanced chromosome segregation in mitosis occurs through complex spatial and temporal regulation of enzyme activities, particularly kinases, phosphatases and enzymes of the ubiquitin cascade. Mitosis also involves highly dynamic and structural reorganization of nuclear and cytoplasmic organelles. Of particular interest in this project are the molecular mechanics of chromosome attachment to and movement on the microtubules of the mitotic spindle. The other main focus is cell cycle control of enzyme activities and their consequences for regulating mitotic progression and the mitotic spindle checkpoint. The mitotic spindle checkpoint is essential in ensuring the normal distribution of chromosomes. It is often defective in cancer cells and it plays a key role in the response of cells to therapeutic anti-cancer drugs such as paclitaxel. The current proposal consists of three aims. Two of the aims are focused on characterization of an entirely novel protein called Kinetochore Protein 1 (Kinp1). Preliminary data indicate that Kinp1 plays an essential role in normal microtubule-kinetochore attachment and/or in regulation of the mitotic spindle checkpoint. The other aim is focused on the general role of nuclear envelope integrity in controlling early events in mitosis. Accomplishing the goals proposed will add significantly to our understanding of cell cycle control of cell division in normal cells and contribute toward understanding how these controls become aberrant in chromosomal imbalances that contribute to human disease such as birth defects and cancer.

Public Health Relevance

This project seeks to define novel aspects of the regulation of cell division in normal and cancer cells. Many of the control mechanisms in cancer cells are abnormal in cancer and these differences provide opportunities to target cancer cells specifically with new therapies. This project will also help us to understand how many current cancer therapies target cells and thus how these therapies can be improved. The results from this study will also enlighten the mechanisms that contribute to chromosome imbalances that are the cause of many birth defects.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CB-D (02))
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Gindhart, Joseph G
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Oklahoma Medical Research Foundation
Oklahoma City
United States
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Sivakumar, Sushama; Daum, John R; Tipton, Aaron R et al. (2014) 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
Daum, John R; Potapova, Tamara A; Sivakumar, Sushama et al. (2011) Cohesion fatigue induces chromatid separation in cells delayed at metaphase. Curr Biol 21:1018-24
Potapova, Tamara A; Sivakumar, Sushama; Flynn, Jennifer N et al. (2011) Mitotic progression becomes irreversible in prometaphase and collapses when Wee1 and Cdc25 are inhibited. Mol Biol Cell 22:1191-206
Wang, Fangwei; Dai, Jun; Daum, John R et al. (2010) Histone H3 Thr-3 phosphorylation by Haspin positions Aurora B at centromeres in mitosis. Science 330:231-5
Gorbsky, Gary J (2010) Duct tape for broken chromosomes. Cell 140:178-80
Daum, John R; Mo, Yin Yuan; Gorbsky, Gary J (2009) The dynamics of DNA topoisomerase IIalpha in living cells. Methods Mol Biol 582:233-44
Salmela, Anna-Leena; Pouwels, Jeroen; Varis, Asta et al. (2009) Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the mitotic spindle checkpoint. Carcinogenesis 30:1032-40
Daum, John R; Wren, Jonathan D; Daniel, Jeremy J et al. (2009) Ska3 is required for spindle checkpoint silencing and the maintenance of chromosome cohesion in mitosis. Curr Biol 19:1467-72
Knowlton, Anne L; Vorozhko, Valeriya V; Lan, Weijie et al. (2009) ICIS and Aurora B coregulate the microtubule depolymerase Kif2a. Curr Biol 19:758-63
DeMoe, Joanna H; Santaguida, Stefano; Daum, John R et al. (2009) A high throughput, whole cell screen for small molecule inhibitors of the mitotic spindle checkpoint identifies OM137, a novel Aurora kinase inhibitor. Cancer Res 69:1509-16

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