A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility
No citation available. Published: 2005.09.29
Jennifer L. Shepard*, James F. Amatruda*, Howard M. Stern, Aravind Subramanian, David Finkelstein, James Ziai, K. Rose Finley, Kathleen L. Pfaff, Candace Hersey, Yi Zhou, Bruce Barut, Matthew Freedman, Charles Lee, Jan Spitsbergen, Donna Neuberg, Gerhard Weber, Todd R. Golub, Jonathan N. Glickman, Jeffery L. Kutok, Jon C. Aster, and Leonard I. Zon
Read ManuscriptAbstract
A major goal of cancer research has been to identify new 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 1,2. Here we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), which 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 mitotic spindle formation, and exhibit genomic 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 loss of the B-myb gene signature is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and surprisingly demonstrate that loss of function of bmyb is associated with cancer.
Keywords: Zebrafish,bmyb,cancer,GSEA,KSS
Supplemental Data
| Description | Link/Filename |
|---|---|
| MAGE formatted zebra fish crb mutant expression dataset | bmyb.zip |
| Whitehead gct formatted zebra fish crb mutant expression dataset | crash_and_burn.gct |
| Class labels for the zebra fish expression dataset | crash_and_burn.cls |
| Global Cancer Map (GCM) dataset | GCM_All.gct |
| Acute Lymphoblastic Leukemia (Golub et al) | ALL_vs_AML_U95_test.res |
| Adenocarcinoma with p53 mutation status (Beer et al) | beer_lung_for_p53.gct |
| Anaplastic Oligodendroglioma (Nutt et al) | glioma_classic_hist.gct |
| Classic Glioblastoma (Nutt et al) | glioma_classic_hist.gct |
| Glioblastoma Survival (Nutt et al) | glioma_nutt_combo.gct |
| Hepatic Carcinoma (Iizuka et al) | hep_japan.gct |
| Lung Adenocarcinoma Outcome (Beer et al) | lung_annarbor_outcome_only.gct |
| Lung Cancer Outcome (Bhatacharjee et al) | lung_datasetB_outcome.gct |
| Lymph Node Metastatic Gastric Adenocarcinoma (Chen et al) | gastric_full_from_smad.paired_14.f1.5_g0.6.pcl |
| Medulloblastoma (McDonald et al) | med_macdonald_from_childrens.gct |
| Medulloblastoma (Pomeroy et al) | medullo_datasetC_outcome.gct |
| Metastatic Tumors (Ramawamy et al) | met.gct |
| References to published datasets used in this analysis | references_and_URLS_of_datasets.html |
| Bmyb signature -- with expression levels (Table S1 full) | bymb_signature_genes.htm |
| Bmyb signature -- list of unique human genes | bmyb_crb_plus_signature_genes.html |
| Zebra fish p53 mutant and wild type CEL files | zebrafish_p53_cel_files.zip |
| Zebra fish HU, Aph and control CEL files | zebrafish_HU_APH_and_control_sphase_cel_files.zip |
| Zebra fish 8g and MO treatment CEL files | zebrafish_8g_and_mo_CEL_files.zip |
| Zebra fish bmyb crb, mo and control CEL files | zebrafish_bmyb_crb_mo_and_control_CEL_files.zip |
| Zebra fish cyclin WT and mutant CEL files | zebrafish_cyclin_wt_and_mutant_CEL_files.zip |
| README for a description of zebrafish datasets used | README_FOR_INFO_ON_ZF_DATASETS.html |