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Cellular senescence mediated by p16INK4A-coupled miRNA pathways.

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.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Overhoff MG,Garbe JC,Koh J,Stampfer MR,Beach DH,Bishop CL

doi

10.1093/nar/gkt1096

subject

Has Abstract

pub_date

2014-02-01 00:00:00

pages

1606-18

issue

3

eissn

0305-1048

issn

1362-4962

pii

gkt1096

journal_volume

42

pub_type

杂志文章

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