Journal
JOURNAL OF CELL BIOLOGY
Volume 181, Issue 7, Pages 1055-1063Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200802105
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Funding
- NCI NIH HHS [CA098193, CA77735, R56 CA077735, R01 CA098139, R01 CA077735, R01 CA098193] Funding Source: Medline
- NIDDK NIH HHS [R21 DK073324, DK73324] Funding Source: Medline
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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.
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