The aneuploidy that is phenotypic of many cancer cells can result from defects in chromosome segregation or failures in cytokinesis. The investigator is using C. elegans as a model system to study the role of chromosomes and the mitotic spindle midzone in the stabilization of the cleavage furrow and the completion of cytokinesis. The C. elegans AIR-2 kinase appears to have an important role in these events. AIR-2 is initially localized to metaphase chromosomes, but moves to the spindle midzone at anaphase. Disruption of AIR-2 expression results in the production of unicellular embryos that execute multiple cell cycles in the absence of cytokinesis. The investigator hypothesizes the AIR-2 kinase is an upstream component of the signaling pathway between the midzone microtubules and the cell cortex that is required for the completion of cytokinesis. The movement of AIR-2 from the chromosomes to the spindle midzone may recruit other proteins to the midzone that are downstream components of this signaling cascade. The current experimental goals are to identify these proteins as well as those acting upstream oI AIR-2 that arc required for the dynamic subcellular localization of AIR-2. The molecular components of the AIR-2 pathway will be identified by: 1) examining the relationship between the AIR-2 kinase and Eg5, a motor protein that is localized to the spindle midzone, 2) cloning the genes for five mutants that phenocopy loss of AIR-2 expression, 3) performing molecular screens for substrates and other proteins that interact with the AIR-2 kinase, 4) isolating extragenic enhancers and suppressors of a temperature-sensitive hypomorphic allele of air-2. The delineation of the AIR-2 regulatory pathway in C. elegans may lead to an understanding of, and the ability to interfere with, the oncogenic potential of the mammalian orthologs of AER-2.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062181-04
Application #
6711745
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Deatherage, James F
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
4
Fiscal Year
2004
Total Cost
$225,000
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Richie, Christopher T; Bembenek, Joshua N; Chestnut, Barry et al. (2011) Protein phosphatase 5 is a negative regulator of separase function during cortical granule exocytosis in C. elegans. J Cell Sci 124:2903-13
Deyter, Gary M R; Furuta, Tokiko; Kurasawa, Yasuhiro et al. (2010) Caenorhabditis elegans cyclin B3 is required for multiple mitotic processes including alleviation of a spindle checkpoint-dependent block in anaphase chromosome segregation. PLoS Genet 6:e1001218
Riefler, Gary M; Dent, Sharon Y R; Schumacher, Jill M (2008) Tousled-mediated activation of Aurora B kinase does not require Tousled kinase activity in vivo. J Biol Chem 283:12763-8
Heallen, Todd R; Adams, Henry P; Furuta, Tokiko et al. (2008) An Afg2/Spaf-related Cdc48-like AAA ATPase regulates the stability and activity of the C. elegans Aurora B kinase AIR-2. Dev Cell 15:603-16
de Carvalho, Carlos Egydio; Zaaijer, Sophie; Smolikov, Sarit et al. (2008) LAB-1 antagonizes the Aurora B kinase in C. elegans. Genes Dev 22:2869-85
Burrows, Anna E; Sceurman, Bonnielin K; Kosinski, Mary E et al. (2006) The C. elegans Myt1 ortholog is required for the proper timing of oocyte maturation. Development 133:697-709
Bishop, John D; Han, Zhenbo; Schumacher, Jill M (2005) The Caenorhabditis elegans Aurora B kinase AIR-2 phosphorylates and is required for the localization of a BimC kinesin to meiotic and mitotic spindles. Mol Biol Cell 16:742-56
Han, Zhenbo; Riefler, Gary M; Saam, Jennifer R et al. (2005) The C. elegans Tousled-like kinase contributes to chromosome segregation as a substrate and regulator of the Aurora B kinase. Curr Biol 15:894-904
Zhang, Ke; Lin, Wenchu; Latham, John A et al. (2005) The Set1 methyltransferase opposes Ipl1 aurora kinase functions in chromosome segregation. Cell 122:723-34
Han, Zhenbo; Saam, Jennifer R; Adams, Henry P et al. (2003) The C. elegans Tousled-like kinase (TLK-1) has an essential role in transcription. Curr Biol 13:1921-9

Showing the most recent 10 out of 13 publications