A mutation in separase causes genome instability and increased susceptibility to epithelial cancer
- Shepard, J.L., Amatruda, J.F., Finkelstein, D., Ziai, J., Finley, K.R., Stern, H.M., Chiang, K., Hersey, C., Barut, B., Freeman, J.L., Lee, C., Glickman, J.N., Kutok, J.L., Aster, J.C., and Zon, L.I.
- Genes & Development 21(1): 55-59 (Journal)
- Registered Authors
- Amatruda, James F., Barut, Bruce, Freeman, Jennifer, Hersey, Candace, Lee, Charles, Shepard, Jennifer, Stern, Howard, Ziai, James, Zon, Leonard I.
- Cancer, chromosome segregation, mitotic checkpoint, zebrafish
- MeSH Terms
- Carcinoma, Pancreatic Ductal/etiology
- Carcinoma, Pancreatic Ductal/pathology
- Cell Cycle
- Cell Cycle Proteins/genetics*
- Disease Susceptibility*
- Embryo, Nonmammalian/cytology
- Embryo, Nonmammalian/metabolism
- Genomic Instability*
- Intestinal Neoplasms/etiology
- Intestinal Neoplasms/pathology
- Neoplasms, Glandular and Epithelial/etiology*
- Neoplasms, Glandular and Epithelial/pathology
- Spindle Apparatus/genetics
- Spindle Apparatus/pathology
- Zebrafish/growth & development
- 17210788 Full text @ Genes & Dev.
Shepard, J.L., Amatruda, J.F., Finkelstein, D., Ziai, J., Finley, K.R., Stern, H.M., Chiang, K., Hersey, C., Barut, B., Freeman, J.L., Lee, C., Glickman, J.N., Kutok, J.L., Aster, J.C., and Zon, L.I. (2007) A mutation in separase causes genome instability and increased susceptibility to epithelial cancer. Genes & Development. 21(1):55-59.
Proper chromosome segregation is essential for maintenance of genomic integrity and instability resulting from failure of this process may contribute to cancer. Here, we demonstrate that a mutation in the mitotic regulator separase is responsible for the cell cycle defects seen in the zebrafish mutant, cease&desist (cds). Analysis of cds homozygous mutant embryos reveals high levels of polyploidy and aneuploidy, spindle defects, and a mitotic exit delay. Carcinogenesis studies demonstrated that cds heterozygous adults have a shift in tumor spectrum with an eightfold increase in the percentage of fish bearing epithelial tumors, indicating that separase is a tumor suppressor gene in vertebrates. These data strongly support a conserved cross-species role for mitotic checkpoint genes in genetic stability and epithelial carcinogenesis.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes