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      Cell size and invasion in TGF-β–induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway

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      The Journal of Cell Biology

      The Rockefeller University Press

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          Abstract

          Epithelial to mesenchymal transition (EMT) occurs during development and cancer progression to metastasis and results in enhanced cell motility and invasion. Transforming growth factor-β (TGF-β) induces EMT through Smads, leading to transcriptional regulation, and through non-Smad pathways. We observe that TGF-β induces increased cell size and protein content during EMT. This translational regulation results from activation by TGF-β of mammalian target of rapamycin (mTOR) through phosphatidylinositol 3-kinase and Akt, leading to the phosphorylation of S6 kinase 1 and eukaryotic initiation factor 4E–binding protein 1, which are direct regulators of translation initiation. Rapamycin, a specific inhibitor of mTOR complex 1, inhibits the TGF-β–induced translation pathway and increase in cell size without affecting the EMT phenotype. Additionally, rapamycin decreases the migratory and invasive behavior of cells that accompany TGF-β–induced EMT. The TGF-β–induced translation pathway through mTOR complements the transcription pathway through Smads. Activation of mTOR by TGF-β, which leads to increased cell size and invasion, adds to the role of TGF-β–induced EMT in cancer progression and may represent a therapeutic opportunity for rapamycin analogues in cancer.

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          Most cited references 57

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          Assays of isolated single sympathetic neurones show that their transmitter functions can be either adrenergic or cholinergic depending on growth conditions. The data suggest that the number of transmitters made by most mature individual neurones is restricted.
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              Purification of a membrane-associated protein complex required for protein translocation across the endoplasmic reticulum.

               Ryan Walter,  G Blobel (1980)
              The capacity of microsomal membranes to translocate nascent presecretory proteins across their lipid bilayer can be largely abolished by extracting them with high ionic strength buffers. It can be reconstituted by adding the salt extract back to the depleted membranes [Warren, G. & Doberstein, B. (1978) Nature (London) 273, 569-571]. Utilizing hydrophobic chromatography, we purified to homogeneity a protein component of the salt extract that reconstitutes the translocation activity of the extracted membranes. This component behaves as a homogeneous species upon gel filtration, ion-exchange chromatography, adsorption chromatography, and sucrose-gradient centrifugation. When examined by polyacrylamide gel electrophoresis in NaDodSO4, six polypeptides with apparent Mr of 72,000, 68,000, 54,000, 19,000, 14,000, and 9000 are observed in about equal and constant stoichiometry, suggesting that they are subunits of a complex. The sedimentation coefficient of 11S is in good agreement with the sum of the Mr of the subunits. The Mr 68,000 and 9000 subunits label intensely with N-[3H]ethylmaleimide. Thus, the reported sulfhydryl group requirement of the translocation activity in the unfractionated extract [Jackson, R. C., Walter, P. & Blobel, G. (1980) Nature (London), 286, 174-176] may be localized to either or both the Mr 68,000 and 9000 subunits of the purified complex.
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                Author and article information

                Journal
                J Cell Biol
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                30 July 2007
                : 178
                : 3
                : 437-451
                Affiliations
                Department of Cell and Tissue Biology, Program in Cell Biology, University of California, San Francisco, San Francisco, CA 94143
                Author notes

                Correspondence to Rik Derynck: rik.derynck@ 123456ucsf.edu

                Article
                200611146
                10.1083/jcb.200611146
                2064840
                17646396
                Copyright © 2007, The Rockefeller University Press
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                Research Articles
                Article

                Cell biology

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