Abstract

The long-term goal of this project is to dissect the mechanism that regulates vertebrate chromosome segregation. This process is regulated by three kinases: Cdc2, plkl and Aurora/Ipll. Our approach is to determine how these kinases are themselves regulated and then determine how they control chromosome segregation. Aurora/Ipll kinases regulate four different events in chromosome segregation: centrosome separation, chromatin assembly, kinetochore attachment and cytogenesis. When Aurora kinases are misexpressed they can promote anuploidy and transformation, suggesting that the regulation of Aurora kinases regulation. We provide evidence that Aurora kinases are cell cycle regulated by multiple mechanisms and present a powerful in vitro system to dissect these regulatory pathways. The experiments in this proposal will 1) identify the role of Aurora/Ipll cell cycle phosphorylation; 20 identify the cell regulator (s0 of Aurora/Ipll activity; 30 identify the regulators of Aurora/Ipll proteolysis. An emerging programming transformation is that defects in chromosome segregation can cause anuploidy and promote cancer. By focusing on the spatial and temporal control of chromosome segregation, this work should identify both mechanisms of cancer progression and new targets for cancer therapies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM063045-02S1
Application #
6613528
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Zatz, Marion M
Project Start
2001-04-01
Project End
2006-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
2
Fiscal Year
2002
Total Cost
$24,975
Indirect Cost

  Institution

Name
University of Virginia
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904

  Publications

Barnhart-Dailey, Meghan C; Trivedi, Prasad; Stukenberg, P Todd et al. (2017) HJURP interaction with the condensin II complex during G1 promotes CENP-A deposition. Mol Biol Cell 28:54-64
Trivedi, Prasad; Stukenberg, P Todd (2016) A Centromere-Signaling Network Underlies the Coordination among Mitotic Events. Trends Biochem Sci 41:160-174
Stukenberg, P Todd; Burke, Daniel J (2015) Connecting the microtubule attachment status of each kinetochore to cell cycle arrest through the spindle assembly checkpoint. Chromosoma 124:463-80
Eagleson, Gerald; Pfister, Katherine; Knowlton, Anne L et al. (2015) Kif2a depletion generates chromosome segregation and pole coalescence defects in animal caps and inhibits gastrulation of the Xenopus embryo. Mol Biol Cell 26:924-37
Manukyan, Arkadi; Ludwig, Kirsten; Sanchez-Manchinelly, Sergio et al. (2015) A complex of p190RhoGAP-A and anillin modulates RhoA-GTP and the cytokinetic furrow in human cells. J Cell Sci 128:50-60
Banerjee, Budhaditya; Kestner, Cortney A; Stukenberg, P Todd (2014) EB1 enables spindle microtubules to regulate centromeric recruitment of Aurora B. J Cell Biol 204:947-63
Matson, Daniel R; Stukenberg, P Todd (2014) CENP-I and Aurora B act as a molecular switch that ties RZZ/Mad1 recruitment to kinetochore attachment status. J Cell Biol 205:541-54
Zy?kiewicz, Eliza; Stukenberg, P Todd (2014) Xenopus egg extracts as a simplified model system for structure-function studies of dynein regulators. Methods Mol Biol 1136:117-33
Earnshaw, W C; Allshire, R C; Black, B E et al. (2013) Esperanto for histones: CENP-A, not CenH3, is the centromeric histone H3 variant. Chromosome Res 21:101-6
Niedzialkowska, Ewa; Wang, Fangwei; Porebski, Przemyslaw J et al. (2012) Molecular basis for phosphospecific recognition of histone H3 tails by Survivin paralogues at inner centromeres. Mol Biol Cell 23:1457-66

Showing the most recent 10 out of 41 publications