CtBP1 overexpression in keratinocytes perturbs skin homeostasis.
CtBP1 overexpression in keratinocytes perturbs skin homeostasis.
复制标题
DOI：
10.1038/jid.2013.504
复制
发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Deng H;Li F;Li H;Deng Y;Liu J;Wang D;Han G;Wang XJ;Zhang Q
羧基末端结合蛋白1（CtBP 1）是一种具有多种体外靶点的转录共阻遏物，但其体内功能尚不清楚。我们产生了角蛋白5启动子（K5.CtBP1）的角质细胞特异性CtBP 1转基因小鼠，以探测CtBP 1的病理作用。在转基因表达水平与内源性CtBP 1在急性皮肤伤口，K5.CtBP1表皮表现出过度增殖，E-钙粘蛋白的损失，并未能终末分化。已知的与这些过程相关的CtBP 1靶基因，例如，K5.CtBP1皮肤中p21、Brca 1和E-cadherin表达下调。令人惊讶的是，K5.CtBP1幼仔也表现出脱发表型。我们发现，在K5.CtBP1小鼠中，毛囊分化和周期的关键调节因子Distal-less 3（Dlx 3）的表达降低。分子生物学研究表明，CtBP 1直接抑制Dlx 3的转录。一致地，K5.CtBP1小鼠表现出异常毛囊，其中Dlx 3下游靶标Gata 3、Hoxc 13和毛发角蛋白的表达降低。总之，这第一个CtBP 1转基因模型提供了在体外研究预测的某些CtBP 1功能的体内证据，揭示了我们的知识以前未报道的功能和转录活性的CtBP 1的上下文中的上皮间充质相互作用，并建议CtBP 1在毛囊形态发生和分化的发病机制的作用。
Carboxyl-terminal binding protein-1 (CtBP1) is a transcriptional co-repressor with multiple in vitro targets, but its in vivo functions are largely unknown. We generated keratinocyte-specific CtBP1 transgenic mice with a keratin 5 promoter (K5.CtBP1) to probe the pathological roles of CtBP1. At transgene expression levels comparable with endogenous CtBP1 in acute skin wounds, K5.CtBP1 epidermis displayed hyperproliferation, loss of E-cadherin, and failed terminal differentiation. Known CtBP1 target genes associated with these processes, e.g., p21, Brca1, and E-cadherin were down-regulated in K5.CtBP1 skin. Surprisingly, K5.CtBP1 pups also exhibited a hair loss phenotype. We found that expression of the Distal-less 3 (Dlx3), a critical regulator of hair follicle differentiation and cycling, was decreased in K5.CtBP1 mice. Molecular studies revealed that CtBP1 directly suppressed Dlx3 transcription. Consistently, K5.CtBP1 mice displayed abnormal hair follicles with decreased expression of Dlx3 downstream targets Gata3, Hoxc13, and hair keratins. In sum, this first CtBP1 transgenic model provides in vivo evidence for certain CtBP1 functions predicted from in vitro studies, reveals to our knowledge previously unreported functions and transcriptional activities of CtBP1 in the context of epithelial-mesenchymal interplay, and suggest CtBP1 has a pathogenesis role in hair follicle morphogenesis and differentiation.