The accurate transmission of genetic information during the cell cycle is dependent on the correct operation of a spindle assembly checkpoint the monitors the state of chromosome-microtubule attachment. Signals generated at kinetochores and transmitted via a transduction system comprised of Mad and Bub proteins, act to regulate the activity of the anaphase promoting complex (APC) thereby linking cell cycle progression to the correct execution of the mechanical events of mitosis. The goal of this work is to probe the mechanisms of checkpoint gene activation with the goal of defining the upstream events that initiate checkpoint signaling and the downstream events that control APC. In addition, the role played by checkpoint lesions in genomic instability in mice will be examined through the use of conditional alleles in two checkpoint genes. Specifically: (1) The mechanism by which p53-loss rescues the viability of cells lacking a spindle checkpoint will be analyzed in vitro and in vivo (2) The mechanism of action of a recently discovered negative regulator of Mad2 (CMT2) will be analyzed in detail to uncover key aspects of Mad2-mediated checkpoint signaling. (3) The proteins responsible for recruiting Mad and Bub proteins to kinetochores will be studied, with particular emphasis on the members of the Ndc80 complex (4) Bub1, a kinase with dual functions in checkpoint control and chromosome-microtubule attachment will be analyzed using specific mutations that abrogate various functions (5) The potential role of checkpoint lesions in generating chromosome instability and in promoting cancer will be examined in mice using conditional alleles and mouse model off lung cancer development. The molecular analysis of checkpoints will have an impact on two aspects of cancer biology. First, it should help to reveal the mechanism off action of important anti-microtubule chemotherapeutics such as taxol and the vinca alkaloids. These compounds provoke the spindle checkpoint, and lesions in the checkpoint are very likely to alter the effectiveness of these drugs in the clinic. Second, careful study of the spindle checkpoint should clarify the role of chromosome instability on tumor development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA084179-11S1
Application #
8064224
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Spalholz, Barbara A
Project Start
2000-02-01
Project End
2012-02-29
Budget Start
2009-03-01
Budget End
2012-02-29
Support Year
11
Fiscal Year
2010
Total Cost
$50,850
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Foijer, Floris; Albacker, Lee A; Bakker, Bjorn et al. (2017) Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma. Elife 6:
Foijer, Floris; Xie, Stephanie Z; Simon, Judith E et al. (2014) Chromosome instability induced by Mps1 and p53 mutation generates aggressive lymphomas exhibiting aneuploidy-induced stress. Proc Natl Acad Sci U S A 111:13427-32
Foijer, Floris; DiTommaso, Tia; Donati, Giacomo et al. (2013) Spindle checkpoint deficiency is tolerated by murine epidermal cells but not hair follicle stem cells. Proc Natl Acad Sci U S A 110:2928-33
Bialkowska, Agnieszka B; Crisp, Melissa; Bannister, Thomas et al. (2011) Identification of small-molecule inhibitors of the colorectal cancer oncogene Kr├╝ppel-like factor 5 expression by ultrahigh-throughput screening. Mol Cancer Ther 10:2043-51
Orth, James D; Kohler, Rainer H; Foijer, Floris et al. (2011) Analysis of mitosis and antimitotic drug responses in tumors by in vivo microscopy and single-cell pharmacodynamics. Cancer Res 71:4608-16
Hagan, Robert S; Manak, Michael S; Buch, Hakon Kirkeby et al. (2011) p31(comet) acts to ensure timely spindle checkpoint silencing subsequent to kinetochore attachment. Mol Biol Cell 22:4236-46
Foijer, Floris; Draviam, Viji M; Sorger, Peter K (2008) Studying chromosome instability in the mouse. Biochim Biophys Acta 1786:73-82
Cohen, R L; Espelin, C W; De Wulf, P et al. (2008) Structural and functional dissection of Mif2p, a conserved DNA-binding kinetochore protein. Mol Biol Cell 19:4480-91
Shao, Jinyi; Yang, Vincent W; Sheng, Hongmiao (2008) Prostaglandin E2 and Kruppel-like transcription factors synergistically induce the expression of decay-accelerating factor in intestinal epithelial cells. Immunology 125:397-407
Meraldi, Patrick; McAinsh, Andrew D; Rheinbay, Esther et al. (2006) Phylogenetic and structural analysis of centromeric DNA and kinetochore proteins. Genome Biol 7:R23

Showing the most recent 10 out of 17 publications