title: Thrombin induces slug-mediated E-cadherin transcriptional repression and the parallel up-regulation of N-cadherin by a transcription-independent mechanism in RPE cells.
abstract: The proliferation, directional migration to the vitreous and epithelial-mesenchymal transition (EMT) of quiescent, differentiated retinal pigment epithelium (RPE) cells is a major feature in the development of proliferative vitreoretinopathy (PVR) following exposure of the immuno-privileged eye niche to serum components, thrombin among them. We have previously documented thrombin induction of RPE cell proliferation and migration. We here analyzed the effect of thrombin on the E/N cadherin switch, a hallmark of EMT. Results show that thrombin induces the specific repression of epithelial E-cadherin gene transcription, alongside with the up-regulation of mesenchymal N-cadherin protein in RPE cells. We demonstrate, for the first time, that thrombin induces E-cadherin repression by stimulating snail-2 (SLUG) transcription factor expression, and the concomitant up-regulation of N-cadherin through the transcription-independent increase in protein translation promoted by PI3K/PKC-ζ/mTOR signaling. Our present findings suggest that the activation of protease-activated receptor-1 (PAR-1) by thrombin induces EMT of RPE cells, further supporting a central role for thrombin in PVR pathogenesis.
authors: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico, DF, Mexico.
authors: José Prisco
authors: JP
authors: Palma-Nicolás
authors: Ana María
authors: AM
authors: López-Colomé
mesh_terms: D000818:Animals; D001483:Base Sequence; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D044463:Receptor, PAR-1 / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071250:Snail Family Transcription Factors; D058570:TOR Serine-Threonine Kinases; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D018630:Vitreoretinopathy, Proliferative / Q000209:etiology
chemical_list: D015820:Cadherins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D051745:Protein Kinase C-delta; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044463:Receptor, PAR-1; D000071250:Snail Family Transcription Factors; D058570:TOR Serine-Threonine Kinases; D013917:Thrombin; D014157:Transcription Factors; C570099:N-cadherin, rat; C000604407:SNAI1 protein, human; C000604450:Snai2 protein, rat