TY - JOUR
T1 - Contact inhibition modulates intracellular levels of miR-223 in a p27kip1-dependent manner
AU - Armenia, Joshua
AU - Fabris, Linda
AU - Lovat, Francesca
AU - Berton, Stefania
AU - Segatto, Ilenia
AU - D'Andrea, Sara
AU - Ivan, Cristina
AU - Calin, Cascione George A.
AU - Croce, Carlo M.
AU - Colombatti, Alfonso
AU - Vecchione, Andrea
AU - Belletti, Barbara
AU - Baldassarre, Gustavo
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Contact inhibition
KW - P27Kip1
KW - RNA binding
KW - miR-223
UR - http://www.scopus.com/inward/record.url?scp=84898605903&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84898605903&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.1803
DO - 10.18632/oncotarget.1803
M3 - Article
C2 - 24727437
AN - SCOPUS:84898605903
SN - 1949-2553
VL - 5
SP - 1185
EP - 1197
JO - Oncotarget
JF - Oncotarget
IS - 5
ER -