Cellular senescence mediated by p16INK4A-coupled miRNA pathways.
Nucleic Acids Res
; 42(3): 1606-18, 2014 Feb.
Article
em En
| MEDLINE
| ID: mdl-24217920
ABSTRACT
p16 is a key regulator of cellular senescence, yet the drivers of this stable state of proliferative arrest are not well understood. Here, we identify 22 senescence-associated microRNAs (SA-miRNAs) in normal human mammary epithelial cells. We show that SA-miRNAs-26b, 181a, 210 and 424 function in concert to directly repress expression of Polycomb group (PcG) proteins CBX7, embryonic ectoderm development (EED), enhancer of zeste homologue 2 (EZH2) and suppressor of zeste 12 homologue (Suz12), thereby activating p16. We demonstrate the existence of a tight positive feedback loop in which SA-miRNAs activate and re-enforce the expression of other SA-miRNA members. In contrast, PcG members restrain senescence by epigenetically repressing the expression of these SA-miRNAs. Importantly, loss of p16 leads to repression of SA-miRNA expression, intimately coupling this effector of senescence to the SA-miRNA/PcG self-regulatory loop. Taken together, our findings illuminate an important regulatory axis that underpins the transition from proliferation to cellular senescence.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Senescência Celular
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Inibidor p16 de Quinase Dependente de Ciclina
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MicroRNAs
/
Epigênese Genética
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article