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      Sam68 regulates EMT through alternative splicing–activated nonsense-mediated mRNA decay of the SF2/ASF proto-oncogene

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          Abstract

          Expression levels of SF2/ASF are controlled by Sam68 mediated activation of splicing-induced mRNA decay.

          Abstract

          Epithelial-to-mesenchymal transition (EMT) and its reversal (MET) are crucial cell plasticity programs that act during development and tumor metastasis. We have previously shown that the splicing factor and proto-oncogene SF2/ASF impacts EMT/MET through production of a constitutively active splice variant of the Ron proto-oncogene. Using an in vitro model, we now show that SF2/ASF is also regulated during EMT/MET by alternative splicing associated with the nonsense-mediated mRNA decay pathway (AS-NMD). Overexpression and small interfering RNA experiments implicate the splicing regulator Sam68 in AS-NMD of SF2/ASF transcripts and in the choice between EMT/MET programs. Moreover, Sam68 modulation of SF2/ASF splicing appears to be controlled by epithelial cell–derived soluble factors that act through the ERK1/2 signaling pathway to regulate Sam68 phosphorylation. Collectively, our results reveal a hierarchy of splicing factors that integrate splicing decisions into EMT/MET programs in response to extracellular stimuli.

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          Epithelial-mesenchymal transitions in development and pathologies.

          Jean Paul Thiery (2003)
          The epithelial-mesenchymal transition (EMT) is a fundamental process governing morphogenesis in multicellular organisms. This process is also reactivated in a variety of diseases including fibrosis and in the progression of carcinoma. The molecular mechanisms of EMT were primarily studied in epithelial cell lines, leading to the discovery of transduction pathways involved in the loss of epithelial cell polarity and the acquisition of a variety of mesenchymal phenotypic traits. Similar mechanisms have also been uncovered in vivo in different species, showing that EMT is controlled by remarkably well-conserved mechanisms. Current studies further emphasise the critical importance of EMT and provide a better molecular and functional definition of mesenchymal cells and how they emerged >500 million years ago as a key event in evolution.
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            Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression.

            Don L. Gibbons, Wei Lin, Chad J. Creighton … (2009)
            Metastatic disease is a primary cause of cancer-related death, and factors governing tumor cell metastasis have not been fully elucidated. Here, we address this question by using tumor cell lines derived from mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. Despite having widespread somatic genetic alterations, the metastasis-prone tumor cells retained a marked plasticity. They transited reversibly between epithelial and mesenchymal states, forming highly polarized epithelial spheres in three-dimensional culture that underwent epithelial-to-mesenchymal transition (EMT) following treatment with transforming growth factor-beta or injection into syngeneic mice. This transition was entirely dependent on the microRNA (miR)-200 family, which decreased during EMT. Forced expression of miR-200 abrogated the capacity of these tumor cells to undergo EMT, invade, and metastasize, and conferred transcriptional features of metastasis-incompetent tumor cells. We conclude that tumor cell metastasis is regulated by miR-200 expression, which changes in response to contextual extracellular cues.
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              Scatter-factor and semaphorin receptors: cell signalling for invasive growth.

              Paolo Comoglio, Livio Trusolino (2002)
              Malignant disease occurs when neoplastic cells abandon their primary site of accretion, cross tissue boundaries and penetrate the vasculature to colonize distant sites. This process --metastasis--is the aberrant counterpart of a physiological programme for organ regeneration and maintenance. Scatter factors and semaphorins, together with their receptors, help to orchestrate this programme. What are the differences between physiological and pathological activation of these signalling molecules, and can we exploit them therapeutically to prevent metastasis?
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cell Biol
                Journal ID (iso-abbrev): J. Cell Biol
                Journal ID (hwp): jcb
                Title: The Journal of Cell Biology
                Publisher: The Rockefeller University Press
                ISSN (Print): 0021-9525
                ISSN (Electronic): 1540-8140
                Publication date (Print): 4 October 2010
                Volume: 191
                Issue: 1
                Pages: 87-99
                Affiliations
                [1 ]Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), 27100 Pavia, Italy
                [2 ]International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy
                [3 ]Department of Public Health and Cell Biology, University of Rome Tor Vergata, 00133 Rome, Italy
                [4 ]Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy
                Author notes
                Correspondence to Claudia Ghigna: arneri@ 123456igm.cnr.it ; or Giuseppe Biamonti: biamonti@ 123456igm.cnr.it

                C. Ghigna and G. Biamonti contributed equally to this paper.

                C. Valacca’s present address is New York University School of Medicine, Depts. of Cardiothoracic Surgery and Cell Biology, New York University Cancer Institute, New York, NY 10016

                Article
                Publisher ID: 201001073
                DOI: 10.1083/jcb.201001073
                PMC ID: 2953442
                PubMed ID: 20876280
                SO-VID: 646b7195-c9ae-4c27-882f-9c8889bdcd0b
                Copyright © © 2010 Valacca et al.
                License:

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                Date received : 15 January 2010
                Date accepted : 2 September 2010
                Categories
                Subject: Research Articles
                Subject: Article

                ScienceOpen disciplines: Cell biology
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                ScienceOpen disciplines: Cell biology

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