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

T. Tao, S. B. Sondalle, H. Shi, Shizhen Zhu, A. R. Perez-Atayde, J. Peng, S. J. Baserga, A. T. Look

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3852-3867
Number of pages16
JournalOncogene
Volume36
Issue number27
DOIs
StatePublished - Jul 6 2017

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Ribosomal RNA
Neuroblastoma
RNA Precursors
Zebrafish
Small Ribosome Subunits
Sympathetic Nervous System
Peripheral Nervous System
Haploinsufficiency
Penetrance
Ribosomes
Apoptosis
Cell Line
Growth
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Tao, T., Sondalle, S. B., Shi, H., Zhu, S., Perez-Atayde, A. R., Peng, J., ... Look, A. T. (2017). The pre-rRNA processing factor DEF is rate limiting for the pathogenesis of MYCN-driven neuroblastoma. Oncogene, 36(27), 3852-3867. https://doi.org/10.1038/onc.2016.527

The pre-rRNA processing factor DEF is rate limiting for the pathogenesis of MYCN-driven neuroblastoma. / Tao, T.; Sondalle, S. B.; Shi, H.; Zhu, Shizhen; Perez-Atayde, A. R.; Peng, J.; Baserga, S. J.; Look, A. T.

In: Oncogene, Vol. 36, No. 27, 06.07.2017, p. 3852-3867.

Research output: Contribution to journalArticle

Tao, T, Sondalle, SB, Shi, H, Zhu, S, Perez-Atayde, AR, Peng, J, Baserga, SJ & Look, AT 2017, 'The pre-rRNA processing factor DEF is rate limiting for the pathogenesis of MYCN-driven neuroblastoma', Oncogene, vol. 36, no. 27, pp. 3852-3867. https://doi.org/10.1038/onc.2016.527
Tao, T. ; Sondalle, S. B. ; Shi, H. ; Zhu, Shizhen ; Perez-Atayde, A. R. ; Peng, J. ; Baserga, S. J. ; Look, A. T. / The pre-rRNA processing factor DEF is rate limiting for the pathogenesis of MYCN-driven neuroblastoma. In: Oncogene. 2017 ; Vol. 36, No. 27. pp. 3852-3867.
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