Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells
Authors
Mudhasani, Rajini R.Zhu, Zhiqing
Hutvagner, Gyorgy
Eischen, Christine M.
Lyle, Stephen
Hall, Lisa L.
Lawrence, Jeanne B.
Imbalzano, Anthony N.
Jones, Stephen N.
UMass Chan Affiliations
Department of Cancer BiologyDepartment of Biochemistry and Molecular Pharmacology
Department of Cell Biology
Document Type
Journal ArticlePublication Date
2008-07-02Keywords
Animals*Cell Aging
Cell Proliferation
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p16
DNA Damage
Embryo, Mammalian
Fibroblasts
Gene Deletion
Mice
MicroRNAs
Ribonuclease III
*Signal Transduction
Tumor Suppressor Protein p53
Cancer Biology
Cell Biology
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
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.Source
J Cell Biol. 2008 Jun 30;181(7):1055-63. Link to article on publisher's siteDOI
10.1083/jcb.200802105Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39186PubMed ID
18591425Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1083/jcb.200802105