Contact inhibition modulates intracellular levels of miR-223 in a p27kip1-dependent manner

Joshua Armenia, Linda Fabris, Francesca Lovat, Stefania Berton, Ilenia Segatto, Sara D'Andrea, Cristina Ivan, CascioneGeorge A. Calin, Carlo M. Croce, Alfonso Colombatti, Andrea Vecchione, Barbara Belletti, Gustavo Baldassarre

Research output: Contribution to journalArticlepeer-review

Abstract

MicroRNAs (miRs) are a large class of small regulatory RNAs that function as nodes of signaling networks. This implicates that miRs expression has to be finely tuned, as observed during cell cycle progression. Here, using an expression profiling approach, we provide evidence that the CDK inhibitor p27Kip1 regulates miRs expression following cell cycle exit. By using wild type and p27KO cells harvested in different phases of the cell cycle we identified several miRs regulated by p27Kip1 during the G1 to S phase transition. Among these miRs, we identified miR-223 as a miR specifically upregulated by p27Kip1 in G1 arrested cells. Our data demonstrate that p27Kip1 regulated the expression of miR-223, via two distinct mechanisms. p27Kip1 directly stabilized mature miR-223 expression, acting as a RNA binding protein and it controlled E2F1 expression that, in turn, regulated miR- 223 promoter activity. The resulting elevated miR-223 levels ultimately participated to arresting cell cycle progression following contact inhibition. Importantly, this mechanism of growth control was conserved in human cells and deranged in breast cancers. Here, we identify a novel and conserved function of p27Kip1 that, by modulating miR-223 expression, contributes to proper regulation of cell cycle exit following contact inhibition. Thus we propose a new role for miR-223 in the regulation of breast cancer progression.

Original languageEnglish
Pages (from-to)1185-1197
Number of pages13
JournalOncotarget
Volume5
Issue number5
Publication statusPublished - 2014

Keywords

  • Contact inhibition
  • miR-223
  • P27Kip1
  • RNA binding

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

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