Shepard Jennifer L, Amatruda James F, Stern Howard M, Subramanian Aravind, Finkelstein David, Ziai James, Finley K Rose, Pfaff Kathleen L, Hersey Candace, Zhou Yi, Barut Bruce, Freedman Matthew, Lee Charles, Spitsbergen Jan, Neuberg Donna, Weber Gerhard, Golub Todd R, Glickman Jonathan N, Kutok Jeffery L, Aster Jon C, Zon Leonard I
Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13194-9. doi: 10.1073/pnas.0506583102. Epub 2005 Sep 6.
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.
癌症研究的一个主要目标是识别促成癌症形成的基因。斑马鱼与人类肿瘤之间存在相似的病理学特征，而且过去大规模基因筛查在发现人类疾病基因方面取得了成功，这使得斑马鱼成为寻找此类新基因的理想系统。在此，我们表明斑马鱼正向遗传筛选发现了多个细胞增殖突变体，其中一个突变体crash&burn（crb）代表bmyb功能缺失突变，bmyb是一种转录调节因子，也是假定原癌基因家族的成员。crb突变体胚胎在有丝分裂进程和纺锤体形成方面存在缺陷，并表现出基因组不稳定。bmyb对细胞周期蛋白B水平的调节似乎是crb中有丝分裂积累的机制。致癌作用研究显示成年crb杂合子的癌症易感性增加。斑马鱼中与bmyb缺失相关的基因表达特征也与人类肿瘤样本中的保守特征相关，并且B-myb特征基因的下调与p53功能的保留相关。我们的研究结果表明斑马鱼筛查能够揭示癌症相关途径，并证明bmyb功能缺失与癌症有关。
