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Proc Natl Acad Sci U S A DOI:10.1073/pnas.0506583102

A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility.

Publication TypeJournal Article
Year of Publication2005
AuthorsShepard, JL, Amatruda, JF, Stern, HM, Subramanian, A, Finkelstein, D, Ziai, J, K Finley, R, Pfaff, KL, Hersey, C, Zhou, Y, Barut, B, Freedman, M, Lee, C, Spitsbergen, J, Neuberg, D, Weber, G, Golub, TR, Glickman, JN, Kutok, JL, Aster, JC, Zon, LI
JournalProc Natl Acad Sci U S A
Date Published2005 Sep 13
KeywordsAnimals, Cyclin B, Embryo, Nonmammalian, Genetic Predisposition to Disease, Genomic Instability, Mitosis, Mutation, Neoplasms, Proto-Oncogene Proteins c-myb, Spindle Apparatus, Tumor Suppressor Protein p53, Zebrafish

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.


Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID16150706
PubMed Central IDPMC1198999
Grant ListK08 DK061849 / DK / NIDDK NIH HHS / United States
5K08 DK061849 / DK / NIDDK NIH HHS / United States
K08 HL04082 / HL / NHLBI NIH HHS / United States
K08 HL004082 / HL / NHLBI NIH HHS / United States
1R01 HD044930 / HD / NICHD NIH HHS / United States
R01 DK055381 / DK / NIDDK NIH HHS / United States
1R01 DK55381 / DK / NIDDK NIH HHS / United States