Cellular senescence mediated by p16INK4A-coupled miRNA pathways.

Published

Journal Article

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.

Full Text

Cited Authors

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

Published Date

  • February 2014

Published In

Volume / Issue

  • 42 / 3

Start / End Page

  • 1606 - 1618

PubMed ID

  • 24217920

Pubmed Central ID

  • 24217920

Electronic International Standard Serial Number (EISSN)

  • 1362-4962

Digital Object Identifier (DOI)

  • 10.1093/nar/gkt1096

Language

  • eng

Conference Location

  • England