The Aurora kinases are critical regulators of cell division in organisms from yeast to humans. My lab uses C. elegans as a model system for studying the role of these kinases in chromosome and microtubule dynamics. Recently, specific Aurora substrates have been shown to be activators of the Aurora kinases. In 2002, my lab found that phosphorylation of the C. elegans chromosomal passenger protein ICP-1 enhances the activity of the AIR-2 Aurora B kinase. Others have since shown that this property is conserved in human INCENP and Aurora B. We have recently discovered that the C. elegans Tousled kinase TLK-1 is a second substrate activator of AIR-2. Tousled kinases are highly expressed in S-phase and phosphorylate Asf1 chromatin assembly factors. Our findings suggest that Tousled kinases may have mitotic functions and that AIR-2 may act independently of the chromosomal passenger complex. We hypothesize that distinct substrate activators of Aurora B impart specificity for different substrates and cellular functions. To determine the role of Aurora B substrate activators in the C. elegans cell cycle we will: 1) Determine the functional relationship between TLK-1, ASF-1, ICP-1, and AIR-2 in chromosome behavior, 2) Define the molecular differences between the TLK-1/ICP-1/AIR-2 complex and the chromosomal passenger complex, 3) Perform a molecular screen to identify substrates of the ICP-1/AIR-2 and TLK-1/ICP-1/AIR-2 kinase complexes, 4) Perform a yeast genetic screen to isolate additional substrate activators of the AIR-2/Aurora B kinase. Relevance: Aurora kinases are potent oncogenes and are overexpressed in a number of human tumors. Since Aurora substrate activators have the potential to impart spatial, temporal, and substrate specificity to the Aurora kinases, they are sure to be valuable targets for cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062181-09
Application #
7596269
Study Section
Cell Structure and Function (CSF)
Program Officer
Deatherage, James F
Project Start
2001-03-01
Project End
2010-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
9
Fiscal Year
2009
Total Cost
$337,545
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

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