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

David Llobet-Navas, Ruth Rodriguez-Barrueco, Janis de La Iglesia-Vicente, Mireia Olivan, Veronica Castro, Laura Saucedo-Cuevas, Netonia Marshall, Preeti Putcha, Mireia Castillo-Martin, Evan Bardot, Elena Ezhkova, Antonio Iavarone, Carlos Cordon-Cardo, Jose M. Silva

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageEnglish
Pages (from-to)4216-4231
Number of pages16
JournalMolecular and Cellular Biology
Volume34
Issue number23
DOIs
StatePublished - 2014

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