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 Wee1-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 cell shape and the actin cytoskeleton. We have identified a novel pathway controlling Swe1p degradation, whose initiation depends on a family of cytoskeletal proteins called septins. Septin organization appears to respond to cell shape, and can regulate a checkpoint kinase called Hsl1p.
One aim of this proposal is to understand how septins are organized and how that organization responds to cell geometry to act as a shape sensor. In addition to cell shape, the checkpoint responds to several physiological stresses, and a second aim of the proposal is to understand how these stresses regulate swe1p degradation and hence cell cycle progression. Although a 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 cytoskeletal 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.

Public Health Relevance

The research proposed concerns the way in which cells regulate the machinery that drives cell proliferation (the cell cycle). As many diseases, including cancer, stem from inappropriate proliferation of cells, understanding the basic mechanisms that normally control proliferation will allow the development of novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM053050-17
Application #
8258809
Study Section
Nuclear Dynamics and Transport (NDT)
Program Officer
Hamlet, Michelle R
Project Start
1995-08-01
Project End
2013-10-30
Budget Start
2012-05-01
Budget End
2013-10-30
Support Year
17
Fiscal Year
2012
Total Cost
$382,239
Indirect Cost
$137,214
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
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
Theesfeld, Chandra L; Zyla, Trevin R; Bardes, Elaine G S et al. (2003) A monitor for bud emergence in the yeast morphogenesis checkpoint. Mol Biol Cell 14:3280-91

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