title: Transforming Growth Factor-β1 Induced Epithelial Mesenchymal Transition is blocked by a chemical antagonist of translation factor eIF4E.
abstract: The epithelial to mesenchymal transition (EMT) imparts disease-defining properties to epithelial cells in cancer and organ fibrosis. Prior studies identify EMT control points at the level of transcription and translation, and indicate that activation of translation initiation factor 4E (eIF4E) is involved in the mechanisms coordinating these two levels of control. Here we show that 4Ei-1, a specific chemical antagonist of the eIF4E-mRNA cap interaction, potently inhibits transforming growth factor beta 1 (TGF-β1) mediated EMT in lung epithelial cells. Upon treatment with TGF-β1, we observed a rapid recruitment of Snail1 mRNA into the actively translated polysome pool accompanied by accumulation of the EMT transcription factor Snail1 in the nucleus. 4Ei-1 blocks ribosome recruitment to the Snail1 transcript thereby preventing accumulation of the Snail1 protein in the nucleus. Our findings establish an obligatory role for upstream translational control of downstream Snail1-mediated transcriptional events in TGF-β1 induced EMT, and provide proof of concept for efforts to pharmacologically modulate the eIF4E-cap interaction as a means to inhibit pathological EMT in the setting of cancer and organ fibrosis.
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis, MN 55455 USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Smith
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, CA USA.
authors.forename: B
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis, MN 55455 USA.
authors.forename: S
authors.initials: S
authors.lastname: Avdulov
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis, MN 55455 USA.
authors.forename: A
authors.initials: A
authors.lastname: Benyumov
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis, MN 55455 USA.
authors.forename: M
authors.initials: M
authors.lastname: Peterson
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, CA USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455 USA.
authors.forename: A
authors.initials: A
authors.lastname: Okon
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis, MN 55455 USA.
authors.forename: P
authors.initials: P
authors.lastname: Hergert
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455 USA.
authors.forename: J
authors.initials: J
authors.lastname: Braziunas
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455 USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Wagner
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, CA USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Borok
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis, MN 55455 USA.
authors.forename: P B
authors.initials: PB
authors.lastname: Bitterman
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D034904:Lamin Type A / Q000378:metabolism; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D000199:Actins; D039561:Eukaryotic Initiation Factor-4E; D006157:Guanosine Monophosphate; D034904:Lamin Type A; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C523875:7-benzylguanosine 5'-monophosphate; C440308:lamin C; C498862:Acta2 protein, rat