Cancer cells must acquire multiple mutations to evade the many restraints that prevent uncontrolled proliferation. Normal cells are vigilant in maintaining genome integrity (i.e. preventing mutations), but one hallmark of cancer cells is a defect in such self-surveillance and hence genome instability. Checkpoint controls that govern entry into mitosis are essential for maintaining genome integrity during cell proliferation. The Wee 1-family kinases that inhibit Cdc2 are among the targets for these checkpoints both in mammalian cells and in yeast, but the basis for their regulation remains unclear. In budding yeast, the Wee1-relative Swe1p is employed by the morphogenesis checkpoint, responding to perturbations of the actin cytoskeleton. We have identified a novel pathway controlling Swe1p degradation, and shown that one step in this pathway is regulated by the local geometry of the cell cortex, linking cell shape to biochemical events controlling cell proliferation. We will investigate how it is that specific proteins monitor cell shape and probe other aspects of cytoskeletal organization that appear to be monitored as well. Although the morphogenesis checkpoint has not yet been identified in cells other than yeast, appropriate responses of mammalian cells to geometrical and mechanical features of their microenvironment are thought to involve """"""""sensing"""""""" of similar types of information. The metastatic potential of cancer cells increases upon derangement of these pathways, and the proposed studies will therefore provide new insight into cancer progression, and may yield potential targets for therapeutic intervention. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM053050-10A1
Application #
6873540
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Zatz, Marion M
Project Start
1995-08-01
Project End
2008-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
10
Fiscal Year
2005
Total Cost
$301,520
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
King, Kindra; Kang, Hui; Jin, Michelle et al. (2013) Feedback control of Swe1p degradation in the yeast morphogenesis checkpoint. Mol Biol Cell 24:914-22
Chen, Hsin; Kuo, Chun-Chen; Kang, Hui et al. (2012) Cdc42p regulation of the yeast formin Bni1p mediated by the effector Gic2p. Mol Biol Cell 23:3814-26
Howell, Audrey S; Lew, Daniel J (2012) Morphogenesis and the cell cycle. Genetics 190:51-77
Chen, Hsin; Howell, Audrey S; Robeson, Alex et al. (2011) Dynamics of septin ring and collar formation in Saccharomyces cerevisiae. Biol Chem 392:689-97
Lew, Daniel J; Rout, Michael P (2009) Cell structure and dynamics. Curr Opin Cell Biol 21:1-3
Crutchley, John; King, Kindra M; Keaton, Mignon A et al. (2009) Molecular dissection of the checkpoint kinase Hsl1p. Mol Biol Cell 20:1926-36
Keaton, Mignon A; Szkotnicki, Lee; Marquitz, Aron R et al. (2008) Nucleocytoplasmic trafficking of G2/M regulators in yeast. Mol Biol Cell 19:4006-18
Keaton, Mignon A; Bardes, Elaine S G; Marquitz, Aron R et al. (2007) Differential susceptibility of yeast S and M phase CDK complexes to inhibitory tyrosine phosphorylation. Curr Biol 17:1181-9
McNulty, John J; Lew, Daniel J (2005) Swe1p responds to cytoskeletal perturbation, not bud size, in S. cerevisiae. Curr Biol 15:2190-8
Harrison, Jacob C; Zyla, Trevin R; Bardes, Elaine S G et al. (2004) Stress-specific activation mechanisms for the ""cell integrity"" MAPK pathway. J Biol Chem 279:2616-22

Showing the most recent 10 out of 28 publications