|A zebrafish bmyb mutation causes
genome instability and increased cancer susceptibility
|Abstract|| || A major goal of cancer research has been to identify new 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 1,2. Here we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), which 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 mitotic spindle formation, and exhibit genomic 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 loss of the B-myb gene signature is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and surprisingly demonstrate that loss of function of bmyb is associated with cancer.
|Authors||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. Aster, and Leonard I. Zon|
|Publication Date||09/30/2005||Contact emails||