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-beta (TGF-beta) induces EMT through Smads, leading to transcriptional regulation, and through non-Smad pathways. We observe that TGF-beta induces increased cell size and protein content during EMT. This translational regulation results from activation by TGF-beta 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-beta-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-beta-induced EMT. The TGF-beta-induced translation pathway through mTOR complements the transcription pathway through Smads. Activation of mTOR by TGF-beta, which leads to increased cell size and invasion, adds to the role of TGF-beta-induced EMT in cancer progression and may represent a therapeutic opportunity for rapamycin analogues in cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antibiotics, Antineoplastic / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Adhesion / physiology
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Cell Cycle Proteins
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Cell Movement / physiology
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Cell Size*
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Enzyme Activation
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Epithelial Cells* / cytology
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Epithelial Cells* / physiology
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Epithelium / physiology*
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Eukaryotic Initiation Factors
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Female
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Gene Expression Regulation
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Humans
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Mammary Glands, Animal / anatomy & histology
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Mesoderm / physiology*
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Mice
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Ribosomal Protein S6 Kinases, 70-kDa / genetics
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction / physiology*
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Sirolimus / metabolism
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TOR Serine-Threonine Kinases
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Transforming Growth Factor beta / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Antibiotics, Antineoplastic
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Carrier Proteins
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Cell Cycle Proteins
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Eif4ebp1 protein, mouse
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Eukaryotic Initiation Factors
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Phosphoproteins
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Receptors, Transforming Growth Factor beta
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Transforming Growth Factor beta
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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Sirolimus