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Generation of immortalised but unstable cells after hTERT introduction in telomere-compromised and p53-deficient vHMECS
Bernal, Aina (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Zafon, Elisenda (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Domínguez, Daniel (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Bertran García de Olalla, Enric (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Tusell Padrós, Laura (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)

Date: 2018
Abstract: Telomeres, the natural ends of chromosomes, hide the linear telomeric DNA from constitutive exposure to the DNA damage response with a lariat structure or t-loop. Progressive telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in t-loop collapse and unmasked telomeres. Dysfunctional telomeres can suppress cancer development by engaging replicative senescence or apoptosis, but they can also promote tumour initiation when cell cycle checkpoints are disabled. In this setting, telomere dysfunction promotes increasing chromosome instability (CIN) through breakage-fusion-bridge cycles. Excessive instability may hamper cell proliferation but might allow for the appearance of some rare advantageous mutations that could be selected and ultimately favour neoplastic progression. With the aim of generating pre-malignant immortalised cells, we ectopically expressed telomerase in telomere-compromised variant human mammary epithelial cells (vHMECs), proficient and deficient for p53, and analysed structural and numerical chromosomal aberrations as well as abnormal nuclear morphologies. Importantly, this study provides evidence that while immortalisation of vHMECs at early stages results in an almost stable karyotype, a transient telomere-dependent CIN period—aggravated by p53 deficiency—and followed by hTERT overexpression serves as a mechanism for the generation of immortal unstable cells which, due to their evolving karyotype, could attain additional promoting properties permissive to malignancy.
Note: Número d'acord de subvenció MINECO/SAF2013-43801-P
Note: Número d'acord de subvenció UAB/456-01-1/2012
Note: Número d'acord de subvenció AGAUR/2017-SGR-503
Rights: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Language: Anglès.
Document: article ; recerca ; publishedVersion
Published in: International Journal of Molecular Sciences, Vol. 19 Núm. 7 (17 2018) , p. 2078, ISSN 1422-0067

DOI: 10.3390/ijms19072078
PMID: 30018248


21 p, 2.3 MB

The record appears in these collections:
Articles > Research articles
Articles > Published articles

 Record created 2019-01-29, last modified 2019-10-16



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