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首页> 美国卫生研究院文献>The FASEB Journal >Transcriptional regulation of bone morphogenetic protein 4 by tumor necrosis factor and its relationship with age-related macular degeneration
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Transcriptional regulation of bone morphogenetic protein 4 by tumor necrosis factor and its relationship with age-related macular degeneration

机译：肿瘤坏死因子对骨形态发生蛋白4的转录调控及其与年龄相关性黄斑变性的关系

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Bone morphogenetic protein-4 (BMP4) may be involved in the molecular switch that determines which late form of age-related macular degeneration (AMD) an individual develops. BMP4 expression is high in retinal pigment epithelium (RPE) cells in late, dry AMD patients, while BMP4 expression is low in the wet form of the disease, characterized by choroidal neovascularization (CNV). Here, we sought to determine the mechanism by which BMP4 is down-regulated in CNV. BMP4 expression was decreased within laser-induced CNV lesions in mice at a time when tumor necrosis factor (TNF) expression was high (7 d postlaser) and was reexpressed in RPE when TNF levels declined (14 d postlaser). We found that TNF, an important angiogenic stimulus, significantly down-regulates BMP4 expression in cultured human fetal RPE cells, ARPE-19 cells, and RPE cells in murine posterior eye cup explants. We identified two specificity protein 1 (Sp1) binding sites in the BMP4 promoter that are required for basal expression of BMP4 and its down-regulation by TNF. Through c-Jun NH2-terminal kinase (JNK) activation, TNF modulates Sp1 phosphorylation, thus decreasing its affinity to the BMP4 promoter. The down-regulation of BMP4 expression by TNF in CNV and mechanisms established might be useful for defining novel targets for AMD therapy.—Xu, J., Zhu, D., He, S., Spee, C., Ryan, S. J., Hinton, D. R. Transcriptional regulation of bone morphogenetic protein 4 by tumor necrosis factor and its relationship with age-related macular degeneration.
机译：骨形态发生蛋白4（BMP4）可能参与分子开关，该开关决定了个体发展出哪种年龄相关的黄斑变性（AMD）。在干燥的晚期AMD患者的视网膜色素上皮（RPE）细胞中，BMP4表达高，而在湿性疾病中，BMP4表达低，其特征是脉络膜新血管形成（CNV）。在这里，我们试图确定BMP4在CNV中被下调的机制。当肿瘤坏死因子（TNF）表达高时（激光后7 d），小鼠中激光诱导的CNV病变内BMP4表达降低，而当TNF水平下降（激光后14 d）时，RMP中BMP4表达重新表达。我们发现TNF，一种重要的血管生成刺激物，可显着下调培养的人胎RPE细胞，ARPE-19细胞和鼠眼后杯外植体中RPE细胞中的BMP4表达。我们在BMP4启动子中确定了两个特异性蛋白1（Sp1）结合位点，这对于BMP4的基础表达及其由TNF的下调是必需的。通过c-Jun NH2-末端激酶（JNK）激活，TNF调节Sp1磷酸化，从而降低其对BMP4启动子的亲和力。 TNF在CNV中对BMP4表达的下调及其建立的机制可能对确定AMD治疗的新靶标有用。—Xu，J.，Zhu，D.，He，S.，Spee，C.，Ryan，SJ， Hinton，DR肿瘤坏死因子对骨形态发生蛋白4的转录调控及其与年龄相关性黄斑变性的关系。

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