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 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.
Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK, Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA and Division of Surgical Sciences, Department of Surgery, Duke University Medical School, Durham, NC 27710, USA.
Marita G
MG
Overhoff
James C
JC
Garbe
James
J
Koh
Martha R
MR
Stampfer
David H
DH
Beach
Cleo L
CL
Bishop
D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D044127:Epigenesis, Genetic; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D019941:Cyclin-Dependent Kinase Inhibitor p16; D035683:MicroRNAs; D063146:Polycomb-Group Proteins