title: A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility.
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 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.
authors.affiliation: Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Shepard
authors.forename: James F
authors.initials: JF
authors.lastname: Amatruda
authors.forename: Howard M
authors.initials: HM
authors.lastname: Stern
authors.forename: Aravind
authors.initials: A
authors.lastname: Subramanian
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.forename: James
authors.initials: J
authors.lastname: Ziai
authors.forename: K Rose
authors.initials: KR
authors.lastname: Finley
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Pfaff
authors.forename: Candace
authors.initials: C
authors.lastname: Hersey
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Bruce
authors.initials: B
authors.lastname: Barut
authors.forename: Matthew
authors.initials: M
authors.lastname: Freedman
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Jan
authors.initials: J
authors.lastname: Spitsbergen
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Gerhard
authors.initials: G
authors.lastname: Weber
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Glickman
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
mesh_terms: 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
chemical_list: D019926:Cyclin B; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb; D016159:Tumor Suppressor Protein p53