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.
Copyright © 2012 Wiley Periodicals, Inc.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Base Sequence
-
Cadherins / antagonists & inhibitors
-
Cadherins / genetics
-
Cadherins / metabolism*
-
Cells, Cultured
-
Down-Regulation / drug effects
-
Epithelial-Mesenchymal Transition / drug effects
-
Epithelial-Mesenchymal Transition / genetics
-
Epithelial-Mesenchymal Transition / physiology
-
Humans
-
Mechanistic Target of Rapamycin Complex 1
-
Multiprotein Complexes
-
Nerve Tissue Proteins / genetics
-
Nerve Tissue Proteins / metabolism*
-
Phosphatidylinositol 3-Kinases / metabolism
-
Protein Kinase C-delta / metabolism
-
Proteins / metabolism
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
RNA, Small Interfering / genetics
-
Rats
-
Receptor, PAR-1 / metabolism
-
Retinal Pigment Epithelium / cytology
-
Retinal Pigment Epithelium / drug effects*
-
Retinal Pigment Epithelium / metabolism*
-
Signal Transduction / drug effects
-
Snail Family Transcription Factors
-
TOR Serine-Threonine Kinases
-
Thrombin / metabolism
-
Thrombin / pharmacology*
-
Transcription Factors / antagonists & inhibitors
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
-
Transcription, Genetic / drug effects
-
Up-Regulation / drug effects
-
Vitreoretinopathy, Proliferative / etiology
Substances
-
Cadherins
-
Multiprotein Complexes
-
N-cadherin, rat
-
Nerve Tissue Proteins
-
Proteins
-
RNA, Messenger
-
RNA, Small Interfering
-
Receptor, PAR-1
-
SNAI1 protein, human
-
Snai2 protein, rat
-
Snail Family Transcription Factors
-
Transcription Factors
-
Mechanistic Target of Rapamycin Complex 1
-
TOR Serine-Threonine Kinases
-
Protein Kinase C-delta
-
Thrombin