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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 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.

Pubmed ID: 16150706


  • Shepard JL
  • Amatruda JF
  • Stern HM
  • Subramanian A
  • Finkelstein D
  • Ziai J
  • Finley KR
  • 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


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

September 13, 2005

Associated Grants

  • Agency: NIDDK NIH HHS, Id: 1R01 DK55381
  • Agency: NICHD NIH HHS, Id: 1R01 HD044930
  • Agency: NIDDK NIH HHS, Id: 5K08 DK061849
  • Agency: NHLBI NIH HHS, Id: K08 HL04082

Mesh Terms

  • Animals
  • 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