PUBLICATION
A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility
- Authors
- Shepard, J.L., Amatruda, J.F., Stern, H.M., Subramanian, A., Finkelstein, D., Ziai, J., Finley, K.R., Pfaff, K.L., Hersey, C., Zhou, Y., Barut, B., Freedman, M., Lee, C., Spitsbergen, J., Neuberg, D., Weber, G., Golub, T.R., Glickman, J.N., Kutok, J.L., Aster, J.C., and Zon, L.I.
- ID
- ZDB-PUB-050913-4
- Date
- 2005
- Source
- Proceedings of the National Academy of Sciences of the United States of America 102(37): 13194-13199 (Journal)
- Registered Authors
- Amatruda, James F., Barut, Bruce, Hersey, Candace, Lee, Charles, Pfaff, Kathleen, Shepard, Jennifer, Spitsbergen, Jan, Stern, Howard, Zhou, Yi, Ziai, James, Zon, Leonard I.
- Keywords
- none
- MeSH Terms
-
- Animals
- Cyclin B/metabolism
- Embryo, Nonmammalian
- Genetic Predisposition to Disease
- Genomic Instability*
- Mitosis
- Mutation*
- Neoplasms/etiology
- Neoplasms/genetics*
- Proto-Oncogene Proteins c-myb/genetics*
- Spindle Apparatus
- Tumor Suppressor Protein p53
- Zebrafish
- PubMed
- 16150706 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Shepard, J.L., Amatruda, J.F., Stern, H.M., Subramanian, A., Finkelstein, D., Ziai, J., Finley, K.R., Pfaff, K.L., Hersey, C., Zhou, Y., Barut, B., Freedman, M., Lee, C., Spitsbergen, J., Neuberg, D., Weber, G., Golub, T.R., Glickman, J.N., Kutok, J.L., Aster, J.C., and Zon, L.I. (2005) A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility. Proceedings of the National Academy of Sciences of the United States of America. 102(37):13194-13199.
Abstract
A major goal of cancer research has been to identify genes that contribute to cancer formation. The similar pathology between zebrafish and human tumors, as well as the past success of large-scale genetic screens in uncovering human disease genes, makes zebrafish an ideal system in which to find such new genes. Here, we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), that represents a loss-of-function mutation in bmyb, a transcriptional regulator and member of a putative proto-oncogene family. crb mutant embryos have defects in mitotic progression and spindle formation, and exhibit genome instability. Regulation of cyclin B levels by bmyb appears to be the mechanism of mitotic accumulation in crb. Carcinogenesis studies reveal increased cancer susceptibility in adult crb heterozygotes. Gene-expression signatures associated with loss of bmyb in zebrafish are also correlated with conserved signatures in human tumor samples, and down-regulation of the B-myb signature genes is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and demonstrate that loss of function of bmyb is associated with cancer.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping