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Mol Biol Cell. 2010 Jul 1;21(13):2138-49. doi: 10.1091/mbc.E10-01-0062. Epub 2010 May 12.

MiR-322/424 and -503 are induced during muscle differentiation and promote cell cycle quiescence and differentiation by down-regulation of Cdc25A.

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  • 1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

Abstract

Induction of a G1 phase cell cycle arrest, caused primarily by the inhibition of cyclin-dependent-kinase 2 (cdk2), is a critical step in the differentiation of myoblasts into myotubes. Here, we report that two microRNAs, miR-322/424 and miR-503, are induced and promote cdk2 inhibition during myogenesis. These microRNAs down-regulate Cdc25A, the phosphatase responsible for removing inhibitory phosphorylation of cdk2, both in myoblasts differentiating into myotubes and in nonmuscle cells. Cdc25A is down-regulated during muscle differentiation by multiple pathways: action of these two microRNAs, proteasomal degradation of Cdc25A protein and transcriptional repression. Overexpression of Cdc25A or of cdk2 with mutations on T14 and Y15 (cdk2-AF), so that it cannot be inhibited by phosphorylation, decreases differentiation and differentiation-induced cell cycle quiescence. Introduction of miR-322/424 and miR-503 in heterologous cancer cells induces G1 arrest, which is also attenuated by overexpression of the cdk2-AF mutant. Until now Cdc25A and the inhibitory phosphorylation on T14 and Y15 of cdk2 have only been implicated in the intra-S phase checkpoint pathway after DNA damage. Our results reveal an unexpected role of Cdc25A down-regulation and the inhibitory phosphorylation of cdk2 T14 and Y15 in cell cycle quiescence during muscle differentiation and implicate two muscle differentiation-induced microRNAs in the process.

PMID:
20462953
[PubMed - indexed for MEDLINE]
PMCID:
PMC2893979
Free PMC Article
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