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MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells.
Zanotti, Sofia; Vanhauwaert, Suzanne; Van Neste, Christophe; Olexiouk, Volodimir; Van Laere, Jolien; Verschuuren, Marlies; Van der Meulen, Joni; Mus, Liselot M; Durinck, Kaat; Tilleman, Laurentijn; Deforce, Dieter; Van Nieuwerburgh, Filip; Hogarty, Michael D; Decaesteker, Bieke; De Vos, Winnok H; Speleman, Frank.
Afiliación
  • Zanotti S; Laboratory of Cell Biology and Histology, Dept. Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
  • Vanhauwaert S; Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium.
  • Van Neste C; Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium.
  • Olexiouk V; Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium.
  • Van Laere J; Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium.
  • Verschuuren M; Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium.
  • Van der Meulen J; Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium.
  • Mus LM; Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium.
  • Durinck K; Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium.
  • Tilleman L; Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium.
  • Deforce D; Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium.
  • Van Nieuwerburgh F; Laboratory of Cell Biology and Histology, Dept. Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
  • Hogarty MD; Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium.
  • Decaesteker B; Cancer Research Institute Ghent (CRIG), Ghent University, 9000, Ghent, Belgium.
  • De Vos WH; Molecular Diagnostic, Ghent University, 9000, Ghent, Belgium.
  • Speleman F; Center for Medical Genetics, Dept. Biomolecular Medicine, Ghent University, Medical Research Building (MRB), 2nd Floor, Entrance 34, Corneel Heymanslaan 10, 9000, Ghent, Belgium.
Sci Rep ; 11(1): 14454, 2021 07 14.
Article en En | MEDLINE | ID: mdl-34262099
MYCN is an oncogenic driver in neural crest-derived neuroblastoma and medulloblastoma. To better understand the early effects of MYCN activation in a neural-crest lineage context, we profiled the transcriptome of immortalized human retina pigment epithelial cells with inducible MYCN activation. Gene signatures associated with elevated MYC/MYCN activity were induced after 24 h of MYCN activation, which attenuated but sustained at later time points. Unexpectedly, MYCN activation was accompanied by reduced cell growth. Gene set enrichment analysis revealed a senescence-like signature with strong induction of p53 and p21 but in the absence of canonical hallmarks of senescence such as ß-galactosidase positivity, suggesting incomplete cell fate commitment. When scrutinizing the putative drivers of this growth attenuation, differential gene expression analysis identified several regulators of nucleolar stress. This process was also reflected by phenotypic correlates such as cytoplasmic granule accrual and nucleolar coalescence. Hence, we propose that the induction of MYCN congests the translational machinery, causing nucleolar stress and driving cells into a transient pre-senescent state. Our findings shed new light on the early events induced by MYCN activation and may help unravelling which factors are required for cells to tolerate unscheduled MYCN overexpression during early malignant transformation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína Proto-Oncogénica N-Myc / Neuroblastoma Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Sci Rep Año: 2021 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína Proto-Oncogénica N-Myc / Neuroblastoma Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Sci Rep Año: 2021 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido