Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells.
Dicer, an enzyme involved in microRNA (miRNA) maturation, is required for proper cell differentiation and embryogenesis in mammals. Recent evidence indicates that Dicer and miRNA may also regulate tumorigenesis. To better characterize the role of miRNA in primary cell growth, we generated Dicer-conditional mice. Ablation of Dicer and loss of mature miRNAs in embryonic fibroblasts up-regulated p19(Arf) and p53 levels, inhibited cell proliferation, and induced a premature senescence phenotype that was also observed in vivo after Dicer ablation in the developing limb and in adult skin. Furthermore, deletion of the Ink4a/Arf or p53 locus could rescue fibroblasts from premature senescence induced by Dicer ablation. Although levels of Ras and Myc oncoproteins appeared unaltered, loss of Dicer resulted in increased DNA damage and p53 activity in these cells. These results reveal that loss of miRNA biogenesis activates a DNA damage checkpoint, up-regulates p19(Arf)-p53 signaling, and induces senescence in primary cells.
Mudhasani
Rajini
R
Department of Cell Biology, University of Massachusetts Medical School, North Worcester, MA 01655, USA.
Zhu
Zhiqing
Z
Hutvagner
Gyorgy
G
Eischen
Christine M
CM
Lyle
Stephen
S
Hall
Lisa L
LL
Lawrence
Jeanne B
JB
Imbalzano
Anthony N
AN
Jones
Stephen N
SN
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004249:DNA Damage; D004622:Embryo, Mammalian / Q000166:cytology / Q000201:enzymology; D005347:Fibroblasts / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D017353:Gene Deletion; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D043244:Ribonuclease III / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D043244:Ribonuclease III