The spindle checkpoint delays the progression from metaphase to anaphase until all condensed chromosomes are properly attached to mitotic spindles. An impaired checkpoint function often results in genomic instability, which predisposes cells to malignant transformation. To understand the molecular basis of functional inactivation of this surveillance mechanism in human cancer development, the Pi's laboratory has focused on the role of BubRl, a key spindle checkpoint kinase, in the maintenance of genomic stability and suppression of tumorigenesis. The Pi's group has generated BubRl+/- mice as well as BubRl+/-ApcMin/+ compound mutant mice. BubRl+/- mice develop intestinal adenocarcinomas at an accelerated rate after azoxymethane treatment. Whereas ApcMin/+ mice develop many adenomatous polyps generally within the small intestine, BubRl+/-ApcMin/+ compound mutant mice develop significantly more spontaneous colonic tumors than ApcMin/+ mice. The colon tumors in BubRl+/-ApcMin/+ mice are clinically more advanced than those observed in ApcMin/+ mice. Moreover, chemopreventive compounds such as sulindac sulfide and S-allylmercaptocysteine are capable of inducing apoptosis in HT-29 and SW-480 colon tumor cells;BubRl - deficient cells are more resistant to apoptosis induced by these compounds. Given that both BubRl and Ape are involved in the regulation of genomic stability in normal cells, we hypothesize that BubRl+/-ApcMin+/- mice would be an excellent rodent model for evaluating the efficacy of anti-tumor activities of various chemopreventive compounds that target colon and understanding the in vivo role of spindle checkpoint components in the maintenance of genomic stability. To test this hypothesis, the Pi's lab will (i) validate and test the chemopreventive effect of sulindac and S-allylmercaptocysteine, which (or the derivative of which) directly target microtubules or mitotic spindles, on suppression of spontaneous intestinal tumorigenesis in BubRl+/- ApcMin/+ compound mutant mice, and (ii) investigate the molecular basis of intestinal carcinogenesis in these mutant mice by studying (a) the genomic instability and the rate of spontaneous transformation of cells deficient in BubRl and/or Ape, (b) the dependence of anti-proliferative effect of sulindac and S-allylmercaptocysteine on the integrity of the spindle checkpoint, and (c) the mechanism by which ApcMin/+ mice shift in tumor burden from the small intestine to colon in the BubRl-deficient genetic background. The long-term goal of this project is to elucidate the mechanism by which cell cycle checkpoints and the Wnt signaling pathway regulate cell proliferation and differentiation as well as genomic stability.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA113349-04
Application #
7682059
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
2006-08-24
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$295,185
Indirect Cost
Name
New York University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Yao, Yixin; Dai, Wei (2012) Mitotic checkpoint control and chromatin remodeling. Front Biosci (Landmark Ed) 17:976-83
Yang, Feikun; Huang, Ying; Dai, Wei (2012) Sumoylated BubR1 plays an important role in chromosome segregation and mitotic timing. Cell Cycle 11:797-806
Yang, Feikun; Hu, Liyan; Chen, Cheng et al. (2012) BubR1 is modified by sumoylation during mitotic progression. J Biol Chem 287:4875-82
Xu, Dazhong; Yao, Yixin; Lu, Luo et al. (2010) Plk3 functions as an essential component of the hypoxia regulatory pathway by direct phosphorylation of HIF-1alpha. J Biol Chem 285:38944-50
Xu, Han-Zhang; Huang, Ying; Wu, Ying-Li et al. (2010) Pharicin A, a novel natural ent-kaurene diterpenoid, induces mitotic arrest and mitotic catastrophe of cancer cells by interfering with BubR1 function. Cell Cycle 9:2897-907
Liu, Xue-Song; Zhao, Xu-Dong; Wang, Xiaoxing et al. (2010) Germinal Cell Aplasia in Kif18a Mutant Male Mice Due to Impaired Chromosome Congression and Dysregulated BubR1 and CENP-E. Genes Cancer 1:26-39
Xu, Dazhong; Yao, Yixin; Jiang, Xuejun et al. (2010) Regulation of PTEN stability and activity by Plk3. J Biol Chem 285:39935-42
Huang, Ying; Yao, Yixin; Xu, Han-Zhang et al. (2009) Defects in chromosome congression and mitotic progression in KIF18A-deficient cells are partly mediated through impaired functions of CENP-E. Cell Cycle 8:2643-9
Rao, Chinthalapally V; Yamada, Hiroshi Y; Yao, Yixin et al. (2009) Enhanced genomic instabilities caused by deregulated microtubule dynamics and chromosome segregation: a perspective from genetic studies in mice. Carcinogenesis 30:1469-74
Dai, Wei (2009) Suppression of genomic instabilities caused by chromosome mis-segregation: a perspective from studying BubR1 and Sgo1. J Formos Med Assoc 108:904-11