ZFIN ID: ZDB-PUB-150311-20
Tumor-specific signaling to p53 is mimicked by Mdm2 inactivation in zebrafish: insights from mdm2 and mdm4 mutant zebrafish
Chua, J.S., Liew, H.P., Guo, L., Lane, D.P.
Date: 2015
Source: Oncogene   34(48): 5933-41 (Journal)
Registered Authors: Lane, David P., Liew, Hoe Peng
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified/embryology
  • Animals, Genetically Modified/genetics
  • Animals, Genetically Modified/metabolism*
  • Blotting, Western
  • Embryo, Nonmammalian/metabolism
  • Embryo, Nonmammalian/pathology
  • Eye Neoplasms/genetics
  • Eye Neoplasms/metabolism
  • Eye Neoplasms/pathology*
  • Gene Expression Regulation, Developmental
  • Mice
  • Mutation/genetics*
  • Phenotype
  • Proto-Oncogene Proteins c-mdm2/genetics
  • Proto-Oncogene Proteins c-mdm2/metabolism*
  • RNA, Messenger/genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tumor Suppressor Protein p53/genetics
  • Tumor Suppressor Protein p53/metabolism*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 25746004 Full text @ Oncogene
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ABSTRACT
In mice, the deletion of either Mdm2 or Mdm4 results in a p53-dependent embryonic lethality. We used zinc-finger nucleases to construct mutations in the mdm2 and mdm4 genes of zebrafish. Although the loss of mdm2 results in a p53-dependent early embryonic lethality, mdm4 mutant fish are viable and grow to adulthood. We also found that an in-frame five-amino acid deletion in mdm2 creates a novel hypomorphic allele. The lethal phenotype observed in the mdm2 mutant fish could be partially rescued by injecting mRNA encoding functional Mdm2, and this required the E3 ligase activity of the protein. Complete rescue was obtained by crossing the mdm2 mutant fish onto a p53M214K mutant background. Although p53 mutant fish on a wild-type mdm2 background were shown to accumulate high levels of p53 protein specifically in tumor tissues, we detected extensive staining of p53 in many normal tissues of the mdm2-p53M214K double-mutant fish. Our results are suggestive of the hypothesis that p53 protein accumulates during tumor formation as a result of tumor-specific inactivation of the Mdm2 pathway.Oncogene advance online publication, 9 March 2015; doi:10.1038/onc.2015.57.
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