ZFIN ID: ZDB-PUB-170307-1
The pre-rRNA processing factor DEF is rate limiting for the pathogenesis of MYCN-driven neuroblastoma
Tao, T., Sondalle, S.B., Shi, H., Zhu, S., Perez-Atayde, A.R., Peng, J., Baserga, S.J., Look, A.T.
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:
  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Expression
  • Haploinsufficiency
  • Humans
  • N-Myc Proto-Oncogene Protein/physiology*
  • Neuroblastoma/genetics
  • Neuroblastoma/metabolism*
  • Neuroblastoma/pathology
  • Nuclear Proteins/physiology*
  • RNA Processing, Post-Transcriptional
  • RNA, Ribosomal, 18S/genetics
  • RNA, Ribosomal, 18S/metabolism
  • Tumor Burden
  • Zebrafish
  • Zebrafish Proteins/physiology*
PubMed: 28263972 Full text @ Oncogene
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.