A feed-forward regulation of endothelin receptors by c-Jun in human non-pigmented ciliary epithelial cells and retinal ganglion cells.
A feed-forward regulation of endothelin receptors by c-Jun in human non-pigmented ciliary epithelial cells and retinal ganglion cells.
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c-Jun 对人非色素性睫状上皮细胞和视网膜神经节细胞内皮素受体的前馈调节
DOI：
10.1371/journal.pone.0185390
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
He S
中科院分区：
文献类型：
--
作者：
Wang J;Ma HY;Krishnamoorthy RR;Yorio T;He S
c-Jun、c-Jun氨基末端激酶（JNK）和内皮素B（ET B）受体已被证明参与青光眼的发病机制。先前，我们报道了c-Jun和CCAAT/增强子结合蛋白β（C/EBPβ）染色的增加与眼内压（IOP）升高的大鼠神经节细胞层内ETB受体的上调相关。此外，这两种转录因子调节ETB受体在人非色素睫状上皮细胞（HNPE）中的表达。本研究探讨了ET-1上调原代大鼠视网膜神经节细胞（RGCs）和HNPE细胞ET受体的机制。ET-1和ET-3可增加原代培养大鼠RGCs中c-Jun和C/EBPβ的免疫细胞化学染色，并观察到两种转录因子的共定位。ET-1处理HNPE细胞后，AP-1和C/EBPβ的DNA结合活性显著增加，c-Jun和c-Jun-N-末端激酶（JNK）蛋白水平显著升高。ETA或ETB受体的过表达促进了c-Jun的上调，也提高了其启动子活性。此外，C/EBPβ的上调可增强c-Jun的DNA结合和mRNA表达，免疫共沉淀证实了c-Jun与C/EBPβ的相互作用。ET-1处理后，HNPE细胞凋亡被确定，ETA或ETB受体的过表达产生增强的凋亡。ET-1介导的c-Jun和C/EBPβ的上调及其相互作用可能是调节内皮素受体表达的一种新机制。结果表明，ET-1通过ETA和ETB受体上调c-Jun的表达，c-Jun也上调内皮素受体的表达，从而形成内皮素受体激活和表达的正反馈环。这种前馈调节可能有助于ET-1处理后RGC死亡和星形胶质细胞增殖。
c-Jun, c-Jun N-terminal kinase(JNK) and endothelin B (ETB) receptor have been shown to contribute to the pathogenesis of glaucoma. Previously, we reported that an increase of c-Jun and CCAAT/enhancer binding protein β (C/EBPβ) immunohistostaining is associated with upregulation of the ETB receptor within the ganglion cell layer of rats with elevated intraocular pressure (IOP). In addition, both transcription factors regulate the expression of the ETB receptor in human non-pigmented ciliary epithelial cells (HNPE). The current study addressed the mechanisms by which ET-1 produced upregulation of ET receptors in primary rat retinal ganglion cells (RGCs) and HNPE cells. Treatment of ET-1 and ET-3 increased the immunocytochemical staining of c-Jun and C/EBPβ in primary rat RGCs and co-localization of both transcription factors was observed. A marked increase in DNA binding activity of AP-1 and C/EBPβ as well as elevated protein levels of c-Jun and c-Jun-N-terminal kinase (JNK) were detected following ET-1 treatment in HNPE cells. Overexpression of ETA or ETB receptor promoted the upregulation of c-Jun and also elevated its promoter activity. In addition, upregulation of C/EBPβ augmented DNA binding and mRNA expression of c-Jun, and furthermore, the interaction of c-Jun and C/EBPβ was confirmed using co-immunoprecipitation. Apoptosis of HNPE cells was identified following ET-1 treatment, and overexpression of the ETA or ETB receptor produced enhanced apoptosis. ET-1 mediated upregulation of c-Jun and C/EBPβ and their interaction may represent a novel mechanism contributing to the regulation of endothelin receptor expression. Reciprocally, c-Jun was also found to regulate the ET receptors and C/EBPβ appeared to play a regulatory role in promoting expression of c-Jun. Taken together, the data suggests that ET-1 triggers the upregulation of c-Jun through both ETA and ETB receptors, and conversely c-Jun also upregulates endothelin receptor expression, thereby generating a positive feed-forward loop of endothelin receptor activation and expression. This feed-forward regulation may contribute to RGC death and astrocyte proliferation following ET-1 treatment.
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影响因子：
4
作者：
Hess, J;Angel, P;Schorpp-Kistner, M
通讯作者：
Schorpp-Kistner, M
影响因子：
6.1
作者：
Fernandes, Kimberly A.;Harder, Jeffrey M.;Fornarola, Laura B.;Freeman, Robert S.;Clark, Abbot F.;Pang, Iok-Hou;John, Simon W. M.;Libby, Richard T.
通讯作者：
Libby, Richard T.
影响因子：
4.4
作者：
He, Shaoqing;Prasanna, Ganesh;Yorio, Thomas
通讯作者：
Yorio, Thomas
影响因子：
6
作者：
Felx, Melanie;Guyot, Marie-Claude;Moldovan, Florina
通讯作者：
Moldovan, Florina
影响因子：
5.3
作者：
HSU, W;KERPPOLA, TK;CHENKIANG, S
通讯作者：
CHENKIANG, S