title: The pre-rRNA processing factor DEF is rate limiting for the pathogenesis of MYCN-driven neuroblastoma.
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.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tao
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Sondalle
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|College of Animal Sciences, Zhejiang University, Hangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center and Mayo Clinic Center for Individualized Medicine, Rochester, MN, USA.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center and Mayo Clinic Center for Individualized Medicine, Rochester, MN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Perez-Atayde
authors.affiliation: College of Animal Sciences, Zhejiang University, Hangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Peng
authors.affiliation: Departments of Molecular Biophysics &Biochemistry, Genetics and Therapeutic Radiology, Yale University and Yale University School of Medicine, New Haven, CT, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Baserga
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Look
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015870:Gene Expression; D057895:Haploinsufficiency; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein / Q000502:physiology*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional; D012337:RNA, Ribosomal, 18S / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000502:physiology*
chemical_list: D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D012337:RNA, Ribosomal, 18S; C000622696:UTP25 protein, human; D029961:Zebrafish Proteins