Cellular senescence mediated by p16INK4A-coupled miRNA pathways

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 co...

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Bibliographic Details
Published in:Nucleic acids research 2014-02, Vol.42 (3), p.1606-1618
Main Authors: Overhoff, Marita G, Garbe, James C, Koh, James, Stampfer, Martha R, Beach, David H, Bishop, Cleo L
Format: Article
Language:English
Subjects:
BASIC BIOLOGICAL SCIENCES
Biochemistry & Molecular Biology
Cells, Cultured
Cellular Senescence - genetics
Cyclin-Dependent Kinase Inhibitor p16 - metabolism
Epigenesis, Genetic
Feedback, Physiological
Fibroblasts - cytology
Fibroblasts - metabolism
Gene Regulation, Chromatin and Epigenetics
Gene Silencing
Humans
MicroRNAs - metabolism
Polycomb-Group Proteins - genetics
Polycomb-Group Proteins - metabolism
Young Adult
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkt1096