title: The microRNA 424/503 cluster reduces CDC25A expression during cell cycle arrest imposed by transforming growth factor β in mammary epithelial cells.
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.
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Llobet-Navas
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rodriguez-Barrueco
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Janis
authors.initials: J
authors.lastname: de la Iglesia-Vicente
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Mireia
authors.initials: M
authors.lastname: Olivan
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Castro
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Saucedo-Cuevas
authors.affiliation: Institute for Cancer Genetics, Department of Pathology, Irving Cancer Research Center, Columbia University, New York, New York, USA.
authors.forename: Netonia
authors.initials: N
authors.lastname: Marshall
authors.affiliation: Institute for Cancer Genetics, Department of Pathology, Irving Cancer Research Center, Columbia University, New York, New York, USA.
authors.forename: Preeti
authors.initials: P
authors.lastname: Putcha
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo-Martin
authors.affiliation: 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.
authors.forename: Evan
authors.initials: E
authors.lastname: Bardot
authors.affiliation: 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.
authors.forename: Elena
authors.initials: E
authors.lastname: Ezhkova
authors.affiliation: Institute for Cancer Genetics, Department of Pathology, Irving Cancer Research Center, Columbia University, New York, New York, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Iavarone
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.affiliation: 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.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Silva
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development; D042361:Mammary Glands, Human / Q000166:cytology / Q000254:growth & development*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C583557:IGF1 protein, human; C530108:LY2109761; C554214:MIRN424 microrna, human; C545473:MIRN503 microRNA, human; D035683:MicroRNAs; D011720:Pyrazoles; D011758:Pyrroles; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases