Dysfunction of the stress-responsive FOXC1 transcription factor contributes to the earlier-onset glaucoma observed in Axenfeld-Rieger syndrome patients.
Dysfunction of the stress-responsive FOXC1 transcription factor contributes to the earlier-onset glaucoma observed in Axenfeld-Rieger syndrome patients.
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DOI：
10.1038/cddis.2014.8
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发表时间：
2014-02-20
影响因子：
9
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中科院分区：
文献类型：
--
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Forkhead Box C1 (FOXC1) 转录因子基因突变与 Axenfeld-Rieger 综合征 (ARS) 有关，这是一种影响眼前节结构的发育障碍。大约 75% 携带 FOXC1 突变的 ARS 患者会出现早发性青光眼。位于眼前节的小梁网（TM）持续暴露于氧化应激预计是发生青光眼的危险因素。应激诱导的 TM 细胞死亡会导致 TM 功能障碍，导致眼内压升高，这是发生青光眼的主要危险因素。 FOXC1 预计可通过调节对应激反应重要的基因来维持 TM 细胞的稳态。在这项研究中，我们证明热休克 70 蛋白家族的成员 HSPA6 是 FOXC1 的靶基因。 HSPA6 蛋白仅在严重氧化应激条件下诱导，对人小梁网 (HTM) 细胞具有保护功能。我们还表明，FOXC1 具有抗凋亡作用，因为敲低 FOXC1 会显着降低 HTM 细胞的活力。此外，我们还发现 FOXC1 本身会对压力做出反应，因为细胞暴露于 H2O2 诱导的氧化应激会降低 FOXC1 水平和活性。降低 FOXC1 功能的条件，例如细胞暴露于氧化应激和 FOXC1 ARS 突变，会损害 TM 细胞有效应对环境压力的能力。 FOXC1 功能障碍会导致 TM 细胞死亡，这是青光眼发展的重要一步。
Mutations in the Forkhead Box C1 (FOXC1) transcription factor gene are associated with Axenfeld-Rieger syndrome (ARS), a developmental disorder affecting structures in the anterior segment of the eye. Approximately 75% of ARS patients with FOXC1 mutations develop earlier-onset glaucoma. Constant exposure of the trabecular meshwork (TM), located in the anterior segment of the eye, to oxidative stress is predicted to be a risk factor for developing glaucoma. Stress-induced death of TM cells results in dysfunction of the TM, leading to elevated intraocular pressure, which is a major risk factor for developing glaucoma. FOXC1 is predicted to maintain homeostasis in TM cells by regulating genes that are important for stress response. In this study, we show that a member of the heat-shock 70 family of proteins, HSPA6, is a target gene of FOXC1. HSPA6 protein, which is only induced under severe oxidative stress conditions, has a protective function in human trabecular meshwork (HTM) cells. We also show that FOXC1 is anti-apoptotic as knocking down FOXC1 significantly decreases HTM cell viability. In addition, we show that FOXC1 itself responds to stress as exposure of cells to H2O2-induced oxidative stress reduces FOXC1 levels and activity. Conditions that decrease FOXC1 function, such as exposure of cells to oxidative stress and FOXC1 ARS mutations, compromise the ability of TM cells to effectively respond to environmental stresses. Dysfunction of FOXC1 contributes to the death of TM cells, an important step in the development of glaucoma.
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