title: Cyclin A2 modulates EMT via β-catenin and phospholipase C pathways.
abstract: We have previously demonstrated that Cyclin A2 is involved in cytoskeletal dynamics, epithelial-mesenchymal transition (EMT) and metastasis. This phenotype was potentiated by activated oncogenic H-Ras. However, the mechanisms governing EMT in these cells have not yet been elucidated. Here, we dissected the pathways that are responsible for EMT in cells deficient for Cyclin A2. In Cyclin A2-depleted normal murine mammary gland (NMuMG) cells expressing RasV12, we found that β-catenin was liberated from the cell membrane and cell-cell junctions and underwent nuclear translocation and activation. Components of the canonical wingless (WNT) pathway, including WNT8b, WNT10a, WNT10b, frizzled 1 and 2 and TCF4 were upregulated at the messenger RNA and protein levels following Cyclin A2 depletion. However, suppression of the WNT pathway using the acetyltransferase porcupine inhibitor C59 did not reverse EMT whereas a dominant negative form of TCF4 as well as inhibition of phospholipase C using U73122 were able to do so. This suggests that a WNT-independent mechanism of β-catenin activation via phospholipase C is involved in the EMT induced by Cyclin A2 depletion. Our findings will broaden our knowledge on how Cyclin A2 contributes to EMT and metastasis.
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, France-Université Montpellier 2, France-Université Montpellier 1, Montpellier, France.
authors.forename: Caroline T
authors.initials: CT
authors.lastname: Cheung
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, France-Université Montpellier 2, France-Université Montpellier 1, Montpellier, France, UT Southwestern Medical Center, Department of Cell Biology, Dallas, TX, USA and.
authors.forename: Nawal
authors.initials: N
authors.lastname: Bendris
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, France-Université Montpellier 2, France-Université Montpellier 1, Montpellier, France.
authors.forename: Conception
authors.initials: C
authors.lastname: Paul
authors.affiliation: INSERM U982, Neuronal and Neuroendocrine Differentiation and Communication, Université de Rouen, Mont-Saint-Aignan, France.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Hamieh
authors.affiliation: INSERM U982, Neuronal and Neuroendocrine Differentiation and Communication, Université de Rouen, Mont-Saint-Aignan, France.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Anouar
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, France-Université Montpellier 2, France-Université Montpellier 1, Montpellier, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Hahne
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, France-Université Montpellier 2, France-Université Montpellier 1, Montpellier, France, benedicte.lemmers@igmm.cnrs.fr.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Blanchard
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS, France-Université Montpellier 2, France-Université Montpellier 1, Montpellier, France, benedicte.lemmers@igmm.cnrs.fr jean-marie.blanchard@igmm.cnrs.fr.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Lemmers
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D056751:Cyclin A2 / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C508184:CCNA2 protein, mouse; C495267:CTNNB1 protein, mouse; D056751:Cyclin A2; D051176:beta Catenin; D017868:Cyclic AMP-Dependent Protein Kinases; D010738:Type C Phospholipases