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MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells

Sofia Zanotti (UGent) , Suzanne Vanhauwaert (UGent) , Christophe Van Neste (UGent) , Volodimir Olexiouk (UGent) , Jolien Van Laere (UGent) , Marlies Verschuuren, Joni Van der Meulen (UGent) , Liselot Mus (UGent) , Kaat Durinck (UGent) , Laurentijn Tilleman (UGent) , et al.
(2021) SCIENTIFIC REPORTS. 11(1).
Author
Organization
Abstract
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 beta -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.
Keywords
RIBOSOME BIOGENESIS, CELLULAR SENESCENCE, DIFFERENTIATION, AMPLIFICATION, METABOLISM, MECHANISMS, EXPRESSION, INHIBITORS, GENOME, GROWTH

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MLA
Zanotti, Sofia, et al. “MYCN-Induced Nucleolar Stress Drives an Early Senescence-like Transcriptional Program in HTERT-Immortalized RPE Cells.” SCIENTIFIC REPORTS, vol. 11, no. 1, 2021, doi:10.1038/s41598-021-93863-9.
APA
Zanotti, S., Vanhauwaert, S., Van Neste, C., Olexiouk, V., Van Laere, J., Verschuuren, M., … Speleman, F. (2021). MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells. SCIENTIFIC REPORTS, 11(1). https://doi.org/10.1038/s41598-021-93863-9
Chicago author-date
Zanotti, Sofia, Suzanne Vanhauwaert, Christophe Van Neste, Volodimir Olexiouk, Jolien Van Laere, Marlies Verschuuren, Joni Van der Meulen, et al. 2021. “MYCN-Induced Nucleolar Stress Drives an Early Senescence-like Transcriptional Program in HTERT-Immortalized RPE Cells.” SCIENTIFIC REPORTS 11 (1). https://doi.org/10.1038/s41598-021-93863-9.
Chicago author-date (all authors)
Zanotti, Sofia, Suzanne Vanhauwaert, Christophe Van Neste, Volodimir Olexiouk, Jolien Van Laere, Marlies Verschuuren, Joni Van der Meulen, Liselot Mus, Kaat Durinck, Laurentijn Tilleman, Dieter Deforce, Filip Van Nieuwerburgh, Michael D. Hogarty, Bieke Decaesteker, Winnok H. De Vos, and Franki Speleman. 2021. “MYCN-Induced Nucleolar Stress Drives an Early Senescence-like Transcriptional Program in HTERT-Immortalized RPE Cells.” SCIENTIFIC REPORTS 11 (1). doi:10.1038/s41598-021-93863-9.
Vancouver
1.
Zanotti S, Vanhauwaert S, Van Neste C, Olexiouk V, Van Laere J, Verschuuren M, et al. MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells. SCIENTIFIC REPORTS. 2021;11(1).
IEEE
[1]
S. Zanotti et al., “MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells,” SCIENTIFIC REPORTS, vol. 11, no. 1, 2021.
@article{8717667,
  abstract     = {{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 beta -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.}},
  articleno    = {{14454}},
  author       = {{Zanotti, Sofia and Vanhauwaert, Suzanne and Van Neste, Christophe and Olexiouk, Volodimir and Van Laere, Jolien and Verschuuren, Marlies and Van der Meulen, Joni and Mus, Liselot and Durinck, Kaat and Tilleman, Laurentijn and Deforce, Dieter and Van Nieuwerburgh, Filip and Hogarty, Michael D. and Decaesteker, Bieke and De Vos, Winnok H. and Speleman, Franki}},
  issn         = {{2045-2322}},
  journal      = {{SCIENTIFIC REPORTS}},
  keywords     = {{RIBOSOME BIOGENESIS,CELLULAR SENESCENCE,DIFFERENTIATION,AMPLIFICATION,METABOLISM,MECHANISMS,EXPRESSION,INHIBITORS,GENOME,GROWTH}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{15}},
  title        = {{MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells}},
  url          = {{http://doi.org/10.1038/s41598-021-93863-9}},
  volume       = {{11}},
  year         = {{2021}},
}
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