A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility.

Proc Natl Acad Sci U S A
Authors
Keywords
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.

Year of Publication
2005
Journal
Proc Natl Acad Sci U S A
Volume
102
Issue
37
Pages
13194-9
Date Published
2005 Sep 13
ISSN
0027-8424
URL
DOI
10.1073/pnas.0506583102
PubMed ID
16150706
PubMed Central ID
PMC1198999
Links
Grant list
K08 DK061849 / DK / NIDDK NIH HHS / United States
5K08 DK061849 / DK / NIDDK NIH HHS / United States
K08 HL04082 / HL / NHLBI NIH HHS / United States
K08 HL004082 / HL / NHLBI NIH HHS / United States
1R01 HD044930 / HD / NICHD NIH HHS / United States
R01 DK055381 / DK / NIDDK NIH HHS / United States
1R01 DK55381 / DK / NIDDK NIH HHS / United States