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Mol Cell Biol. 2014 Dec 1;34(23):4216-31. doi: 10.1128/MCB.00611-14. Epub 2014 Sep 29.

The microRNA 424/503 cluster reduces CDC25A expression during cell cycle arrest imposed by transforming growth factor β in mammary epithelial cells.

Author information

1
Icahn School of Medicine at Mount Sinai, Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA david.llobet@mssm.edu jose.silva@mssm.edu.
2
Icahn School of Medicine at Mount Sinai, Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA.
3
Institute for Cancer Genetics, Department of Pathology, Irving Cancer Research Center, Columbia University, New York, New York, USA.
4
Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, Department of Development and Regenerative Medicine, Stem Cell Institute, Mount Sinai School of Medicine, New York, New York, USA.

Abstract

Recently, we demonstrated that the microRNA 424(322)/503 [miR-424(322)/503] cluster is transcriptionally controlled by transforming growth factor β (TGF-β) in the mammary epithelium. Induction of this microRNA cluster impacts mammary epithelium fate by regulating apoptosis and insulin-like growth factor 1 (IGF1) signaling. Here, we expanded our finding to demonstrate that miR-424(322)/503 is an integral component of the cell cycle arrest mediated by TGF-β. Mechanistically, we showed that after TGF-β exposure, increased levels of miR-424(322)/503 reduce the expression of the cell cycle regulator CDC25A. miR-424(322)/503-dependent posttranscriptional downregulation of CDC25A cooperates with previously described transcriptional repression of the CDC25A promoter and proteasome-mediated degradation to reduce the levels of CDC25A expression and to induce cell cycle arrest. We also provide evidence that the TGF-β/miR-424(322)/503 axis is part of the mechanism that regulates the proliferation of hormone receptor-positive (HR(+)) mammary epithelial cells in vivo.

PMID:
25266660
PMCID:
PMC4248740
DOI:
10.1128/MCB.00611-14
[Indexed for MEDLINE]
Free PMC Article

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