The Polymorphisms with Cataract Susceptibility Impair the EPHA2 Receptor Stability and Its Cytoprotective Function.
The Polymorphisms with Cataract Susceptibility Impair the EPHA2 Receptor Stability and Its Cytoprotective Function.
复制标题
白内障易感性多态性损害EPHA2受体稳定性及其细胞保护功能
DOI：
10.1155/2015/401894
复制
发表时间：
2015
影响因子：
1.9
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Yang J;Li D;Fan Q;Cai L;Qiu X;Zhou P;Lu Y
尽管越来越多的证据揭示了年龄相关性白内障的易感基因，但其导致视力损害的病理生理学在细胞和分子水平上仍然知之甚少。最近的生物信息学研究揭示了人类EPHA2中两个单核苷酸多态性rs2291806和rs1058371与年龄相关性白内障的关联。在这里，我们研究了EPHA 2在对抗氧化应激诱导的透镜上皮细胞凋亡中的作用。白内障相关的错义突变导致EPHA2受体不稳定，而不改变mRNA转录。EPHA 2在透镜上皮细胞中的细胞保护和抗凋亡功能被功能多态性所取消。此外，我们的研究结果表明，激活的EPHA 2的下游信号促进透镜上皮细胞的抗氧化能力，以消除活性氧的过度产生。相比之下，在透镜上皮细胞中具有非同义突变的EPHA 2的过表达提供了有限的抗氧化保护以对抗氧化应激。因此，我们的研究不仅揭示了在透镜中EPHA 2信号转导的潜在细胞保护功能，而且提供了年龄相关性白内障发病机制的细胞机制。
Despite accumulating evidence revealing susceptibility genes for age-related cataract, its pathophysiology leading to visual impairment at the cellular and molecular level remains poorly understood. Recent bioinformatic studies uncovered the association of two single nucleotide polymorphisms in human EPHA2, rs2291806 and rs1058371, with age-related cataract. Here we investigated the role of EPHA2 in counteracting oxidative stress-induced apoptosis of lens epithelial cells. The cataract-associated missense mutations resulted in the destabilization of EPHA2 receptor without altering the mRNA transcription. The cytoprotective and antiapoptotic function of EPHA2 in lens epithelial cells was abolished by the functional polymorphisms. Furthermore, our results suggest that the downstream signaling of activated EPHA2 promotes the antioxidative capacity of lens epithelial cells to eradicate the overproduction of reactive oxygen species. In contrast, the overexpression of EPHA2 with nonsynonymous mutations in the lens epithelial cells offered limited antioxidative protection against oxidative stress. Thus, our study not only sheds the light on the potential cytoprotective function of EPHA2 signaling in lens but also provides the cellular mechanisms underlying the pathogenesis of age-related cataract.