PUBLICATION

tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors

Authors
Berghmans,, S., Murphey, R.D., Wienholds, E., Neuberg, D., Kutok, J.L., Fletcher, C.D., Morris, J.P., Liu, T.X., Schulte-Merker, S., Kanki, J.P., Plasterk, R., Zon, L.I., and Look, A.T.
ID
ZDB-PUB-050106-6
Date
2005
Source
Proceedings of the National Academy of Sciences of the United States of America   102(2): 407-412 (Journal)
Registered Authors
Kanki, John, Liu, Ting Xi, Look, A. Thomas, Plasterk, Ronald H.A., Schulte-Merker, Stefan, Wienholds, Erno, Zon, Leonard I.
Keywords
none
MeSH Terms
  • Mutation
  • Genes, p53/physiology*
  • Alleles
  • Nerve Sheath Neoplasms/etiology*
  • Zebrafish
  • Animals
  • Apoptosis/radiation effects
(all 7)
PubMed
15630097 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
TP53 is the most frequently mutated tumor suppressor gene in human cancer, with nearly 50% of all tumors exhibiting a loss-of-function mutation. To further elucidate the genetic pathways involving TP53 and cancer, we have exploited the zebrafish, a powerful vertebrate model system that is amenable to whole-genome forward-genetic analysis and synthetic-lethal screens. Zebrafish lines harboring missense mutations in the tp53 DNA-binding domain were identified by using a target-selected mutagenesis strategy. Homozygous mutant fish from two of these lines were viable and exhibited mutations similar to those found in human cancers (tp53(N168K) and tp53(M214K)). Although homozygous tp53(N168K) mutants were temperature-sensitive and suppressed radiation-induced apoptosis only at 37 degrees C, cells in the tp53(M214K) embryos failed to undergo apoptosis in response to gamma radiation at both 28 and 37 degrees C. Unlike wild-type control embryos, irradiated tp53(M214K) embryos also failed to up-regulate p21 and did not arrest at the G1/S checkpoint. Beginning at 8.5 months of age, 28% of tp53(M214K) mutant fish developed malignant peripheral nerve sheath tumors. In addition to providing a model for studying the molecular pathogenic pathways of malignant peripheral nerve sheath tumors, these mutant zebrafish lines provide a unique platform for modifier screens to identify genetic mutations or small molecules that affect tp53-related pathways, including apoptosis, cell-cycle delay, and tumor suppression.
Genes / Markers
Figures
Figure Gallery (4 images)
Show all Figures
Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
zdf1
    		Point Mutation
    zdf2
      		Point Mutation
      zdf3
        		Point Mutation
        zdf4
          		Point Mutation
          zdf5
            		Point Mutation
            1 - 5 of 5
            Show
            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            No data available
            Fish
            Fish
            tp53zdf1/zdf1
            tp53zdf2/zdf2
            tp53zdf3/zdf3
            tp53zdf4/zdf4
            tp53zdf5/zdf5
            TU
            1 - 6 of 6
            Show
            Antibodies
            No data available
            Orthology
            No data available
            Engineered Foreign Genes
            No data available
            Mapping
            No data available
            Your Input Welcome
            We welcome your input and comments. Please use this form to recommend updates to the information in ZFIN. We appreciate as much detail as possible and references as appropriate. We will review your comments promptly.
            Citation
            Berghmans,, S., Murphey, R.D., Wienholds, E., Neuberg, D., Kutok, J.L., Fletcher, C.D., Morris, J.P., Liu, T.X., Schulte-Merker, S., Kanki, J.P., Plasterk, R., Zon, L.I., and Look, A.T. (2005) tp53 mutant zebrafish develop malignant peripheral nerve sheath tumors. Proceedings of the National Academy of Sciences of the United States of America. 102(2):407-412.