A Zebrafish bmyb Mutation Causes Genome Instability and Increased Cancer Susceptibility

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 suc...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 37; pp. 13194 - 13199
Main Authors Shepard, Jennifer L., Amatruda, James F., Stern, Howard M., Subramanian, Aravind, Finkelstein, David, Ziai, James, Finley, K. Rose, Pfaff, Kathleen L., Hersey, Candace, Zhou, Yi, Barut, Bruce, Freedman, Matthew, Lee, Charles, Spitsbergen, Jan, Neuberg, Donna, Weber, Gerhard, Golub, Todd R., Glickman, Jonathan N., Kutok, Jeffery L., Aster, Jon C., Zon, Leonard I., Kunkel, Louis M.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 13.09.2005
National Acad Sciences
Subjects
Aneuploidy
Animals
Biological Sciences
Cancer
Cyclin B - metabolism
Cyclins
Danio rerio
Embryo, Nonmammalian
Embryonic cells
Embryos
Fish
Freshwater
Genes
Genetic mutation
Genetic Predisposition to Disease
Genetic screening
Genomic Instability
Genomics
Mitosis
Mutation
Neoplasms - etiology
Neoplasms - genetics
Proto-Oncogene Proteins c-myb - genetics
Signatures
Spindle Apparatus
Tumor Suppressor Protein p53
Tumors
Zebrafish
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Summary: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.
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Present address: Departments of Pediatrics and Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8593.
Author contributions: J.L.S., J.F.A., and L.I.Z. designed research; J.L.S., J.F.A., H.M.S., D.F., J.Z., K.R.F., K.L.P., C.H., B.B., and M.F. performed research; J.L.S. and J.S. contributed new reagents/analytic tools; J.L.S., J.F.A., H.M.S., A.S., Y.Z., C.L., D.N., G.W., T.R.G., J.N.G., J.L.K., and J.C.A. analyzed data; and J.L.S. and A.S. wrote the paper.
J.L.S. and J.F.A. contributed equally to this work.
To whom correspondence should be addressed. E-mail: zon@enders.tch.harvard.edu.
Communicated by Louis M. Kunkel, Harvard Medical School, Boston, MA, August 1, 2005
Abbreviations: hpf, hours postfertilization; MNNG, N-methyl-N′-nitro-N-nitrosoguanidine; pH3, phosphohistone H3.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0506583102