A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility

Jennifer L. Shepard, James F. Amatruda, Howard M. Stern, Aravind Subramanian, David Finkelstein, James Ziai, K. Rose Finley, Kathleen L. Pfaff, Candace Hersey, Yi Zhou, Bruce Barut, Matthew Freedman, Charles Lee, Jan Spitsbergen, Donna Neuberg, Gerhard Weber, Todd R. Golub, Jonathan N. Glickman, Jeffery L. Kutok, Jon C. AsterLeonard I. Zon

Research output: Contribution to journalArticle

127 Scopus citations

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 protooncogene 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.

Original languageEnglish (US)
Pages (from-to)13194-13199
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number37
DOIs
StatePublished - Sep 13 2005

Keywords

  • Cell cycle

ASJC Scopus subject areas

  • General

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    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., ... 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. https://doi.org/10.1073/pnas.0506583102