KLF4通过转录激活非经典WNT5A来控制上皮分层。
KLF4 transcriptionally activates non-canonical WNT5A to control epithelial stratification.
作者信息
Tetreault Marie-Pier, Weinblatt Daniel, Shaverdashvili Khvaramze, Yang Yizeng, Katz Jonathan P
机构信息
Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA.
出版信息
Sci Rep. 2016 May 17;6:26130. doi: 10.1038/srep26130.
Epithelial differentiation and stratification are essential for normal homeostasis, and disruption of these processes leads to both injury and cancer. The zinc-finger transciption factor KLF4 is a key driver of epithelial differentiation, yet the mechanisms and targets by which KLF4 controls differentiation are not well understood. Here, we define WNT5A, a non-canonical Wnt ligand implicated in epithelial differentiation, repair, and cancer, as a direct transcriptional target that is activated by KLF4 in squamous epithelial cells. Further, we demonstrate functionally that WNT5A mediates KLF4 control of epithelial differentiation and stratification, as treatment of keratinocytes with WNT5A rescues defective epithelial stratification resulting from KLF4 loss. Finally, we show that the small GTPase CDC42 is regulated by KLF4 in a WNT5A dependent manner. As such, we delineate a novel pathway for epithelial differentiation and stratification and define potential therapeutic targets for epithelial diseases.
上皮细胞分化和分层对于正常的体内平衡至关重要，这些过程的破坏会导致损伤和癌症。锌指转录因子KLF4是上皮细胞分化的关键驱动因子，然而KLF4控制分化的机制和靶点尚未完全清楚。在这里，我们将WNT5A定义为鳞状上皮细胞中由KLF4激活的直接转录靶点，WNT5A是一种参与上皮细胞分化、修复和癌症的非经典Wnt配体。此外，我们通过功能实验证明WNT5A介导KLF4对上皮细胞分化和分层的控制，因为用WNT5A处理角质形成细胞可挽救因KLF4缺失导致的上皮分层缺陷。最后，我们表明小GTP酶CDC42以WNT5A依赖的方式受KLF4调控。因此，我们描绘了一条上皮细胞分化和分层的新途径，并确定了上皮疾病的潜在治疗靶点。
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