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Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration

Recent work suggested that the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) is increased in the retinal pigment epithelium (RPE) of age-related macular degeneration (ARMD) patients and therefore could be an attractive therapeutic target. Notably, ERK1/2 pathway inhibitors are used...

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Autores principales: Pyakurel, Aswin, Balmer, Delphine, Saba-El-Leil, Marc K., Kizilyaprak, Caroline, Daraspe, Jean, Humbel, Bruno M., Voisin, Laure, Le, Yun Z., von Lintig, Johannes, Meloche, Sylvain, Roduit, Raphaël
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705814/
https://www.ncbi.nlm.nih.gov/pubmed/29038159
http://dx.doi.org/10.1128/MCB.00295-17
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author Pyakurel, Aswin
Balmer, Delphine
Saba-El-Leil, Marc K.
Kizilyaprak, Caroline
Daraspe, Jean
Humbel, Bruno M.
Voisin, Laure
Le, Yun Z.
von Lintig, Johannes
Meloche, Sylvain
Roduit, Raphaël
author_facet Pyakurel, Aswin
Balmer, Delphine
Saba-El-Leil, Marc K.
Kizilyaprak, Caroline
Daraspe, Jean
Humbel, Bruno M.
Voisin, Laure
Le, Yun Z.
von Lintig, Johannes
Meloche, Sylvain
Roduit, Raphaël
author_sort Pyakurel, Aswin
collection PubMed
description Recent work suggested that the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) is increased in the retinal pigment epithelium (RPE) of age-related macular degeneration (ARMD) patients and therefore could be an attractive therapeutic target. Notably, ERK1/2 pathway inhibitors are used in cancer therapy, with severe and noncharacterized ocular side effects. To decipher the role of ERK1/2 in RPE cells, we conditionally disrupted the Erk1 and Erk2 genes in mouse RPE. The loss of ERK1/2 activity resulted in a significant decrease in the level of RPE65 expression, a decrease in ocular retinoid levels concomitant with low visual function, and a rapid disorganization of RPE cells, ultimately leading to retinal degeneration. Our results identify the ERK1/2 pathway as a direct regulator of the visual cycle and a critical component of the viability of RPE and photoreceptor cells. Moreover, our results caution about the need for a very fine adjustment of kinase inhibition in cancer or ARMD treatment in order to avoid ocular side effects.
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spelling pubmed-57058142017-12-07 Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration Pyakurel, Aswin Balmer, Delphine Saba-El-Leil, Marc K. Kizilyaprak, Caroline Daraspe, Jean Humbel, Bruno M. Voisin, Laure Le, Yun Z. von Lintig, Johannes Meloche, Sylvain Roduit, Raphaël Mol Cell Biol Research Article Recent work suggested that the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) is increased in the retinal pigment epithelium (RPE) of age-related macular degeneration (ARMD) patients and therefore could be an attractive therapeutic target. Notably, ERK1/2 pathway inhibitors are used in cancer therapy, with severe and noncharacterized ocular side effects. To decipher the role of ERK1/2 in RPE cells, we conditionally disrupted the Erk1 and Erk2 genes in mouse RPE. The loss of ERK1/2 activity resulted in a significant decrease in the level of RPE65 expression, a decrease in ocular retinoid levels concomitant with low visual function, and a rapid disorganization of RPE cells, ultimately leading to retinal degeneration. Our results identify the ERK1/2 pathway as a direct regulator of the visual cycle and a critical component of the viability of RPE and photoreceptor cells. Moreover, our results caution about the need for a very fine adjustment of kinase inhibition in cancer or ARMD treatment in order to avoid ocular side effects. American Society for Microbiology 2017-11-28 /pmc/articles/PMC5705814/ /pubmed/29038159 http://dx.doi.org/10.1128/MCB.00295-17 Text en Copyright © 2017 Pyakurel et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Pyakurel, Aswin
Balmer, Delphine
Saba-El-Leil, Marc K.
Kizilyaprak, Caroline
Daraspe, Jean
Humbel, Bruno M.
Voisin, Laure
Le, Yun Z.
von Lintig, Johannes
Meloche, Sylvain
Roduit, Raphaël
Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration
title Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration
title_full Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration
title_fullStr Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration
title_full_unstemmed Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration
title_short Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration
title_sort loss of extracellular signal-regulated kinase 1/2 in the retinal pigment epithelium leads to rpe65 decrease and retinal degeneration
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705814/
https://www.ncbi.nlm.nih.gov/pubmed/29038159
http://dx.doi.org/10.1128/MCB.00295-17
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