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

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
dbh	AB	standard conditions	Protruding-mouth	superior cervical ganglion	ISH	Fig. 1
dbh	utp25^{hi429Tg/hi429Tg} (AB)	standard conditions	Protruding-mouth	superior cervical ganglion	ISH	Fig. 1
EGFP	utp25^{hi429Tg/hi429Tg}; zdf15Tg (AB)	standard conditions	Day 5	superior cervical ganglion	IFL	Fig. 1
EGFP	utp25^hi429Tg/+; zdf15Tg (AB)	standard conditions	Day 5	superior cervical ganglion	IFL	Fig. 1
EGFP	zdf15Tg (AB)	standard conditions	Days 45-89	interrenal gland	IFL	Fig. S1
EGFP	zdf15Tg (AB)	standard conditions	Day 5	superior cervical ganglion	IFL	Fig. 1
EGFP	zdf16Tg (AB)	standard conditions	Adult	interrenal gland neuroblastoma	IFL	Fig. S1
EGFP	zdf16Tg (AB)	standard conditions	Adult	interrenal gland	IFL	Fig. S1
EGFP	zdf30Tg (AB)	standard conditions	Days 45-89	interrenal gland neuroblastoma	IFL	Fig. S1
EGFP	zdf30Tg (AB)	standard conditions	Days 45-89	interrenal gland	IFL	Fig. S1

1 - 10 of 28

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
tp53^zdf1/zdf1; utp25^hi429Tg/+; zdf30Tg (AB)	standard conditions	Days 45-89 to Adult	interrenal gland neoplastic, abnormal	Fig. S2
tp53^zdf1/zdf1; utp25^hi429Tg/+; zdf30Tg (AB)	standard conditions	Days 45-89 to Adult	interrenal gland neuroblastoma present, exacerbated	Fig. S2
utp25^hi429Tg/+; zdf16Tg (AB)	standard conditions	Days 45-89	whole organism tp53 expression increased amount, abnormal	Fig. S2
utp25^hi429Tg/+; zdf30Tg (AB)	standard conditions	Days 30-44	interrenal gland apoptotic process occurrence, exacerbated	Fig. 3
utp25^hi429Tg/+; zdf30Tg (AB)	standard conditions	Days 30-44	interrenal gland cell amount, ameliorated	Fig. 3
utp25^hi429Tg/+; zdf30Tg (AB)	standard conditions	Days 30-44	interrenal gland cell population proliferation occurrence, ameliorated	Fig. 3
utp25^hi429Tg/+; zdf30Tg (AB)	standard conditions	Days 30-44	interrenal gland neuroblastoma proliferative, ameliorated	Fig. 3
utp25^hi429Tg/+; zdf30Tg (AB)	standard conditions	Days 30-44	interrenal gland nucleolus ab10-tp53 labeling increased distribution, abnormal	Fig. S2
utp25^hi429Tg/+; zdf30Tg (AB)	standard conditions	Days 45-89	interrenal gland neuroblastoma size, ameliorated	Fig. 2
utp25^hi429Tg/+; zdf30Tg (AB)	standard conditions	Days 45-89	interrenal gland nucleolus ab1-fbl labeling spatial pattern, ameliorated	Fig. 2

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
hi429Tg	Tg(F5)	Transgenic Insertion	utp25
zdf1		Point Mutation	tp53
zdf15Tg	Tg(dbh:EGFP)	Transgenic Insertion
zdf16Tg	Tg(dbh:EGFP-Hsa.MYCN) Tg(mitfa:mitfa)	Transgenic Insertion
zdf22Tg	Tg(dbh:mCherry)	Transgenic Insertion
zdf30Tg	Tg(dbh:EGFP) Tg(dbh:Hsa.MYCN)	Transgenic Insertion
zdf31Tg	Tg(dbh:Hsa.DIEXF) Tg(dbh:mCherry)	Transgenic Insertion
zdf32Tg	Tg(dbh:Hsa.DIEXF) Tg(dbh:mCherry)	Transgenic Insertion

1 - 8 of 8

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
neuroblastoma	zdf30Tg (AB)	standard conditions	TAS

Sequence Targeting Reagents

Fish

Fish
AB
tp53^zdf1/zdf1; utp25^hi429Tg/+; zdf30Tg (AB)
utp25^{hi429Tg/hi429Tg} (AB)
utp25^{hi429Tg/hi429Tg}; zdf15Tg (AB)
utp25^{hi429Tg/hi429Tg}; zdf30Tg (AB)
utp25^hi429Tg/+; zdf15Tg (AB)
utp25^hi429Tg/+; zdf16Tg (AB)
utp25^hi429Tg/+; zdf30Tg (AB)
zdf15Tg (AB)
zdf16Tg (AB)

1 - 10 of 16

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Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab1-casp3	monoclonal		IgG	Rabbit
Ab1-diexf	polyclonal	utp25		Rabbit
Ab1-elavl	monoclonal	elavl3 elavl4	IgG2b	Mouse
Ab1-fbl	monoclonal	fbl	IgG1	Mouse
Ab2-syp	monoclonal		IgG1	Mouse
Ab2-th	polyclonal	th		Rabbit
Ab2-tuba	monoclonal		IgG1	Mouse
Ab9-gapdh	monoclonal		IgG	Rabbit
Ab10-tp53	monoclonal	tp53		Mouse

1 - 9 of 9

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Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
mCherry	EFG	mCherry

Mapping

Tao et al., 2017 ZDB-PUB-170307-1 PMID:28263972

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

Tao et al., 2017

ZDB-PUB-170307-1
PMID:28263972