RGD Reference Report - Deregulated ERK1/2 MAP kinase signaling promotes aneuploidy by a Fbxw7ß-Aurora A pathway. - Rat Genome Database
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Deregulated ERK1/2 MAP kinase signaling promotes aneuploidy by a Fbxw7ß-Aurora A pathway.

Authors: Duhamel, Stéphanie  Girondel, Charlotte  Dorn, Jonas F  Tanguay, Pierre-Luc  Voisin, Laure  Smits, Ron  Maddox, Paul S  Meloche, Sylvain 
Citation: Duhamel S, etal., Cell Cycle. 2016 Jun 17;15(12):1631-42. doi: 10.1080/15384101.2016.1183851. Epub 2016 May 6.
RGD ID: 13800881
Pubmed: (View Article at PubMed) PMID:27152455
DOI: Full-text: DOI:10.1080/15384101.2016.1183851

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 Fbxw7ß, 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 Fbxw7ß phenocopies the effect of H-Ras(V12) on cell division. In vivo, conditional activation of MEK2 in the mouse intestine lowers Fbxw7ß expression, resulting in the accumulation of cells with enlarged nuclei. We propose that the ERK1/2/ Fbxw7ß/Aurora A axis identified in this study contributes to genomic instability and tumor progression.

Annotation

Disease Annotations    

Objects Annotated

Genes (Rattus norvegicus)
Mapk1  (mitogen activated protein kinase 1)
Mapk3  (mitogen activated protein kinase 3)

Genes (Mus musculus)
Mapk1  (mitogen-activated protein kinase 1)
Mapk3  (mitogen-activated protein kinase 3)

Genes (Homo sapiens)
MAPK1  (mitogen-activated protein kinase 1)
MAPK3  (mitogen-activated protein kinase 3)


Additional Information