Aneuploidy is a hallmark of the vast majority of human solid tumors. Mutations in mitotic checkpoint genes such as BUB1, BUBR1 or MAD2 have been shown to be involved in generation of aneuploidy. These checkpoint gene products forms an intricate signaling network called spindle assembly checkpoint (SAC) that delays the segregation of sister chromatids until all chromosomes are properly attached to the mitotic spindle apparatus and aligned at the metaphase plate. Work from lower organisms such as yeast has clearly demonstrated that loss of the checkpoint function causes chromosomal instability manifested as gains or losses of chromosomes. A more detailed molecular picture of SAC is emerging from analyses in both yeast and higher eukaryotes. However, the function of SAC and its various components at an organismal level remains to be elucidated. Likewise, mechanistic dissection of SAC in mammals is lacking. In an effort to start to molecularly dissect SAC in mammals and to determine its function in preventing chromosomal instability and oncogenic transformation, we generated mouse strains that are defective in SAC to different extents. These strains are securin deletion, non-phosphorylable separase knockin, and Mad2-noninhibitable Cdc20 knockin (AAA-Cdc20). We have found that our AAA-Cdc20 mice were tumor-prone. We propose to address the mechanism by which AAA-Cdc20 promotes tumorigenesis and the role of p53 in limiting tumor development in SAC mutants.

Public Health Relevance

This project focuses on spindle assembly checkpoint's role in the prevention of genome instability and tumorigenesis. Results obtained from the proposed experiments may help the treatment and diagnosis of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122623-03
Application #
7886634
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Mietz, Judy
Project Start
2008-09-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
3
Fiscal Year
2010
Total Cost
$318,513
Indirect Cost
Name
Baylor College of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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