Involvement of the ubiquitin-proteasome system in the expression of extracellular matrix genes in retinal pigment epithelial cells
| العنوان: | Involvement of the ubiquitin-proteasome system in the expression of extracellular matrix genes in retinal pigment epithelial cells |
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| المؤلفون: | J. Emanuel Ramos de Carvalho, Reinier O. Schlingemann, Ilse M. C. Vogels, Milan T. Verwoert, Cornelis J.F. Van Noorden, Eric Reits, Ingeborg Klaassen |
| المساهمون: | Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Graduate School, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Cardiovascular Sciences, Medical Biology, Ophthalmology, ACS - Atherosclerosis & ischemic syndromes, ACS - Microcirculation |
| المصدر: | Biochemistry and Biophysics Reports, Vol 13, Iss, Pp 83-92 (2018) Biochemistry and Biophysics Reports Biochemistry and biophysics reports, 13, 83-92. Elsevier BV |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, PPARγ, TGFβ, transforming growth factor-β, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Gene expression, lcsh:QD415-436, AMD, age-related macular degeneration, lcsh:QH301-705.5, TIMP-1, tissue inhibitor of metalloproteinases-1, biology, FN EDA, fibronectin EDA domain, ECM, extracellular matrix, Cell biology, medicine.anatomical_structure, MMP-2, matrix metalloproteinase-2, ARPE-19, human retinal pigment epithelial cells, RPE, Epoxomicin, EMT, epithelial-mesenchymal transition, Research Article, medicine.drug, RPE, retinal pigment epithelium, Biophysics, Retina, CTGF, connective tissue growth factor, lcsh:Biochemistry, TGFβ, 03 medical and health sciences, PPARγ, peroxisome proliferator-associated receptor-γ, medicine, UPS, ubiquitin-proteasome system, IFNγ, interferon-γ, CNV, choroidal neovascularization, FN, fibronectin, Retinal pigment epithelium, Proteasome, CTGF, nAMD, neovascular age-related macular degeneration, Fibrosis, Fibronectin, 030104 developmental biology, lcsh:Biology (General), chemistry, 030221 ophthalmology & optometry, Proteasome inhibitor, biology.protein, Transforming growth factor |
| الوصف: | Emerging evidence suggests that dysfunction of the ubiquitin-proteasome system is involved in the pathogenesis of numerous senile degenerative diseases including retinal disorders. The aim of this study was to assess whether there is a link between proteasome regulation and retinal pigment epithelium (RPE)-mediated expression of extracellular matrix genes. For this purpose, human retinal pigment epithelial cells (ARPE-19) were treated with different concentrations of transforming growth factor-β (TGFβ), connective tissue growth factor (CTGF), interferon-γ (IFNγ) and the irreversible proteasome inhibitor epoxomicin. First, cytotoxicity and proliferation assays were carried out. The expression of proteasome-related genes and proteins was assessed and proteasome activity was determined. Then, expression of fibrosis-associated factors fibronectin (FN), fibronectin EDA domain (FN EDA), metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinases-1 (TIMP-1) and peroxisome proliferator-associated receptor-γ (PPARγ) was assessed. The proteasome inhibitor epoxomicin strongly arrested cell cycle progression and down-regulated TGFβ gene expression, which in turn was shown to induce expression of pro-fibrogenic genes in ARPE-19 cells. Furthermore, epoxomicin induced a directional shift in the balance between MMP-2 and TIMP-1 and was associated with down-regulation of transcription of extracellular matrix genes FN and FN-EDA and up-regulation of the anti-fibrogenic factor PPARγ. In addition, both CTGF and TGFβ were shown to affect expression of proteasome-associated mRNA and protein levels. Our results suggest a link between proteasome activity and pro-fibrogenic mechanisms in the RPE, which could imply a role for proteasome-modulating agents in the treatment of retinal disorders characterized by RPE-mediated fibrogenic responses. Highlights • CTGF and TGFβ affect transcriptional regulation of proteasome-associated genes. • CTGF induces immunoproteasome activation and proteolytic activity of the proteasome. • TGFβ induces expression of extracellular matrix genes independently of CTGF. • Epoxomicin down-regulates the expression of extracellular matrix genes in RPE cells. • Epoxomicin counteracts TGFβ-mediated down-regulation of PPARγ. |
| اللغة: | English |
| تدمد: | 2405-5808 |
| DOI: | 10.1016/j.bbrep.2018.01.005 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7cb65514a4b0a9eaf3e33367f8adec36 https://doi.org/10.1016/j.bbrep.2018.01.005 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7cb65514a4b0a9eaf3e33367f8adec36 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 24055808 |
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| DOI: | 10.1016/j.bbrep.2018.01.005 |