title: Deregulated ERK1/2 MAP kinase signaling promotes aneuploidy by a Fbxw7β-Aurora A pathway.
abstract: Aneuploidy is a common feature of human solid tumors and is often associated with poor prognosis. There is growing evidence that oncogenic signaling pathways, which are universally dysregulated in cancer, contribute to the promotion of aneuploidy. However, the mechanisms connecting signaling pathways to the execution of mitosis and cytokinesis are not well understood. Here, we show that hyperactivation of the ERK1/2 MAP kinase pathway in epithelial cells impairs cytokinesis, leading to polyploidization and aneuploidy. Mechanistically, deregulated ERK1/2 signaling specifically downregulates expression of the F-box protein Fbxw7β, a substrate-binding subunit of the SCF(Fbxw7) ubiquitin ligase, resulting in the accumulation of the mitotic kinase Aurora A. Reduction of Aurora A levels by RNA interference or pharmacological inhibition of MEK1/2 reverts the defect in cytokinesis and decreases the frequency of abnormal cell divisions induced by oncogenic H-Ras(V12). Reciprocally, overexpression of Aurora A or silencing of Fbxw7β phenocopies the effect of H-Ras(V12) on cell division. In vivo, conditional activation of MEK2 in the mouse intestine lowers Fbxw7β expression, resulting in the accumulation of cells with enlarged nuclei. We propose that the ERK1/2/ Fbxw7β/Aurora A axis identified in this study contributes to genomic instability and tumor progression.
authors.affiliation: a Institute for Research in Immunology and Cancer, Université de Montréal , Montreal , Quebec , Canada.|b Program of Molecular Biology, Université de Montréal , Montreal , Quebec , Canada.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Duhamel
authors.affiliation: a Institute for Research in Immunology and Cancer, Université de Montréal , Montreal , Quebec , Canada.|c Department of Pharmacology , Université de Montréal , Montreal , Quebec , Canada.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Girondel
authors.affiliation: a Institute for Research in Immunology and Cancer, Université de Montréal , Montreal , Quebec , Canada.
authors.forename: Jonas F
authors.initials: JF
authors.lastname: Dorn
authors.affiliation: a Institute for Research in Immunology and Cancer, Université de Montréal , Montreal , Quebec , Canada.
authors.forename: Pierre-Luc
authors.initials: PL
authors.lastname: Tanguay
authors.affiliation: a Institute for Research in Immunology and Cancer, Université de Montréal , Montreal , Quebec , Canada.
authors.forename: Laure
authors.initials: L
authors.lastname: Voisin
authors.affiliation: d Department of Gastroenterology and Hepatology , Erasmus MC , Rotterdam , The Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Smits
authors.affiliation: a Institute for Research in Immunology and Cancer, Université de Montréal , Montreal , Quebec , Canada.|e Department of Pathology and Cell Biology , Université de Montréal , Montreal , Quebec , Canada.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Maddox
authors.affiliation: a Institute for Research in Immunology and Cancer, Université de Montréal , Montreal , Quebec , Canada.|b Program of Molecular Biology, Université de Montréal , Montreal , Quebec , Canada.|c Department of Pharmacology , Université de Montréal , Montreal , Quebec , Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
mesh_terms: D000782:Aneuploidy; D000818:Animals; D064096:Aurora Kinase A / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D048749:Cytokinesis / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics* / Q000378:metabolism; D008938:Mitosis; D051381:Rats; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D044767:Ubiquitin-Protein Ligases; C482128:MAP2K2 protein, human; C576917:AURKA protein, human; D064096:Aurora Kinase A; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048370:MAP Kinase Kinase 2
keywords: Aneuploidy; Aurora A; ERK1/2 MAP kinases; Fbxw7; cytokinesis