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

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Abstract

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

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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