PUBLICATION

The pre-rRNA processing factor DEF is rate limiting for the pathogenesis of MYCN-driven neuroblastoma

Authors
Tao, T., Sondalle, S.B., Shi, H., Zhu, S., Perez-Atayde, A.R., Peng, J., Baserga, S.J., Look, A.T.
ID
ZDB-PUB-170307-1
Date
2017
Source
Oncogene   36(27): 3852-3867 (Journal)
Registered Authors
Look, A. Thomas, Peng, Jinrong, Shi, Hui, Tao, Ting, Zhu, Shizhen
Keywords
none
MeSH Terms
  • Humans
  • RNA Processing, Post-Transcriptional
  • Tumor Burden
  • Nuclear Proteins/physiology*
  • Zebrafish
  • N-Myc Proto-Oncogene Protein/physiology*
  • RNA, Ribosomal, 18S/genetics
  • RNA, Ribosomal, 18S/metabolism
  • Gene Expression
  • Cell Proliferation
  • Cell Line, Tumor
  • Animals
  • Zebrafish Proteins/physiology*
  • Apoptosis
  • Haploinsufficiency
  • Neuroblastoma/genetics
  • Neuroblastoma/metabolism*
  • Neuroblastoma/pathology
(all 18)
PubMed
28263972 Full text @ Oncogene
Abstract
The nucleolar factor, digestive organ expansion factor (DEF), has a key role in ribosome biogenesis, functioning in pre-ribosomal RNA (pre-rRNA) processing as a component of the small ribosomal subunit (SSU) processome. Here we show that the peripheral sympathetic nervous system (PSNS) is very underdeveloped in def-deficient zebrafish, and that def haploinsufficiency significantly decreases disease penetrance and tumor growth rate in a MYCN-driven transgenic zebrafish model of neuroblastoma that arises in the PSNS. Consistent with these findings, DEF is highly expressed in human neuroblastoma, and its depletion in human neuroblastoma cell lines induces apoptosis. Interestingly, overexpression of MYCN in zebrafish and in human neuroblastoma cells results in the appearance of intermediate pre-rRNAs species that reflect the processing of pre-rRNAs through Pathway 2, a pathway that processes pre-rRNAs in a different temporal order than the more often used Pathway 1. Our results indicate that DEF and possibly other components of the SSU processome provide a novel site of vulnerability in neuroblastoma cells that could be exploited for targeted therapy.Oncogene advance online publication, 6 March 2017; doi:10.1038/onc.2016.527.
Genes / Markers
Figures
Figure Gallery (4 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hi429TgTransgenic Insertion
zdf1
    Point Mutation
    zdf15TgTransgenic Insertion
      zdf16TgTransgenic Insertion
        zdf22TgTransgenic Insertion
          zdf30TgTransgenic Insertion
            zdf31TgTransgenic Insertion
              zdf32TgTransgenic Insertion
                1 - 8 of 8
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                Human Disease / Model
                Human Disease Fish Conditions Evidence
                neuroblastomazdf30Tg (AB)standard conditionsTAS
                1 - 1 of 1
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                Sequence Targeting Reagents
                No data available
                Fish
                Antibodies
                Name Type Antigen Genes Isotypes Host Organism
                Ab1-casp3monoclonal
                  IgGRabbit
                  Ab1-diexfpolyclonalRabbit
                  Ab1-elavlmonoclonalIgG2bMouse
                  Ab1-fblmonoclonalIgG1Mouse
                  Ab2-sypmonoclonal
                    IgG1Mouse
                    Ab2-thpolyclonalRabbit
                    Ab2-tubamonoclonal
                      IgG1Mouse
                      Ab9-gapdhmonoclonal
                        IgGRabbit
                        Ab10-tp53monoclonalMouse
                        1 - 9 of 9
                        Show
                        Orthology
                        No data available
                        Engineered Foreign Genes
                        Marker Marker Type Name
                        EGFPEFGEGFP
                        mCherryEFGmCherry
                        1 - 2 of 2
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                        Mapping
                        No data available