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 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. Geneexpression 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.cell cycle

Order, Disorder, Death: Lessons from a Superorganism

“…Drosophila researchers have developed tools for rapid characterization of tumor genes (Potter et al, 2000), and forward genetic approaches in the zebra fish have uncovered cancer pathways (Shepard et al, 2005). Studies of the mouse, in particular, have highlighted the intricacy of cancer: unraveling the faceted interface between the tumor cells and their "host" organism, and the subtle genetic interactions that influence individual susceptibility to disease (Balmain, 2002;Van Dyke and Jacks, 2002).…”

Isolation and functional assessment of common, polymorphic variants of the B-MYB proto-oncogene associated with a reduced cancer risk

“…B-MYB target genes have been found that promote cell cycle progression or resistance to apoptosis, although B-MYB effects might also occur through other mechanisms (Oh and Reddy, 1999;Sala, 2005). While the above described studies support the hypothesis that B-MYB is a proto-oncogene, a recent report shows that an inactivating mutation of B-MYB in zebrafish actually promotes chemical carcinogenesis as a consequence of genomic destabilization (Shepard et al, 2005). Thus, an interesting scenario is emerging where increased B-MYB expression or its inactivating mutations can both result in tumorigenesis.…”

Zebrafish as a Cancer Model

“…In addition, although loss of heterozygosity is expected to be the frequent mechanism in humans to explain the cancer predisposition in individuals with heterozygous tumor suppressor mutations (54), it was hardly ever observed in the comparable zebrafish mutants: not in apc (12), not in all mutant lines of the retroviral insertion screen (24), only once in the whole set of genomic instability mutants (25), twice in the separase mutant (interestingly, these particular mutants did not show a polyploidy phenotype; ref. 13), and never in the bmyb mutant (14). An interesting study in this respect is the N-nitrosodimethylamine induction of liver tumors in triploid and diploid zebrafish (9).…”

“…Homozygous mutant embryos are therefore lethal, and heterozygotes are, due to haploinsufficiency or loss of heterozygosity, predisposed to cancer later in life. Two mutants from this screen have been reported thus far, a loss-of-function mutation in bmyb (14) and a loss-of-function mutation in separase (13), genes that both had not previously been unequivocally implicated in cancer. Homozygous mutant embryos of both displayed mitotic defects and genomic instability, whereas heterozygous adults showed a marginal increase (2-to 2.5-fold) in cancer incidence when treated with N-methyl-N ¶-nitro-N-nitrosoguanidine.…”

“…N-Methyl-N ¶-nitro-N-nitrosoguanidine can also induce different tumor types, mainly liver and testicular neoplasms, as well as hemangio(sarco)mas and others (11). Some of these carcinogenic treatments have been applied to mutants with a genetic predisposition to cancer but a low spontaneous tumor incidence to show an increased sensitivity of mutants compared with treated wild-type animals (12)(13)(14). Not surprisingly, the alkylating mutagen N-ethyl-N-nitrosourea, which introduces point mutations and is commonly used in forward and reverse genetic screens, has also been found to induce cancer.…”