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.
Shepard
Jennifer L
JL
Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
Amatruda
James F
JF
Stern
Howard M
HM
Subramanian
Aravind
A
Finkelstein
David
D
Ziai
James
J
Finley
K Rose
KR
Pfaff
Kathleen L
KL
Hersey
Candace
C
Zhou
Yi
Y
Barut
Bruce
B
Freedman
Matthew
M
Lee
Charles
C
Spitsbergen
Jan
J
Neuberg
Donna
D
Weber
Gerhard
G
Golub
Todd R
TR
Glickman
Jonathan N
JN
Kutok
Jeffery L
JL
Aster
Jon C
JC
Zon
Leonard I
LI
D000818:Animals; D019926:Cyclin B / Q000378:metabolism; D004625:Embryo, Nonmammalian; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D008938:Mitosis; D009154:Mutation; D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics*; D008941:Spindle Apparatus; D016159:Tumor Suppressor Protein p53; D015027:Zebrafish
D019926:Cyclin B; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb; D016159:Tumor Suppressor Protein p53