Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
PLoS One. 2011 Mar 14;6(3):e17685. doi: 10.1371/journal.pone.0017685.
Hair growth is a highly regulated cyclical process. Immunosuppressive immunophilin ligands such as cyclosporin A (CsA) and FK506 are known as potent hair growth modulatory agents in rodents and humans that induce active hair growth and inhibit hair follicle regression. The immunosuppressive effectiveness of these drugs has been generally attributed to inhibition of T cell activation through well-characterized pathways. Specifically, CsA and FK506 bind to intracellular proteins, principally cyclophilin A and FKBP12, respectively, and thereby inhibit the phosphatase calcineurin (Cn). The calcineurin (Cn)/NFAT pathway has an important, but poorly understood, role in the regulation of hair follicle development. Here we show that a novel-splicing variant of calcineurin Aß CnAß-FK, which is encoded by an intron-retaining mRNA and is deficient in the autoinhibitory domain, is predominantly expressed in mature follicular keratinocytes but not in the proliferating keratinocytes of rodents. CnAß-FK was weakly sensitive to Ca(2+) and dephosphorylated NFATc2 under low Ca(2+) levels in keratinocytes. Inhibition of Cn/NFAT induced hair growth in nude mice. Cyclin G2 was identified as a novel target of the Cn/NFATc2 pathway and its expression in follicular keratinocytes was reduced by inhibition of Cn/NFAT. Overexpression of cyclin G2 arrested the cell cycle in follicular keratinocytes in vitro and the Cn inhibitor, cyclosporin A, inhibited nuclear localization of NFATc2, resulting in decreased cyclin G2 expression in follicular keratinocytes of rats in vivo. We therefore suggest that the calcineurin/NFAT pathway has a unique regulatory role in hair follicle development.
头发的生长是一个高度调控的周期性过程。免疫抑制剂免疫亲和素配体，如环孢素 A（CsA）和 FK506，在啮齿动物和人类中被称为强效的毛发生长调节剂，它们可以诱导活跃的毛发生长并抑制毛囊退化。这些药物的免疫抑制效果通常归因于通过特征明确的途径抑制 T 细胞激活。具体来说，CsA 和 FK506 分别与细胞内蛋白（主要是亲环素 A 和 FKBP12）结合，从而抑制磷酸酶钙调神经磷酸酶（Cn）。钙调神经磷酸酶（Cn）/NFAT 途径在调节毛囊发育中具有重要但尚未完全理解的作用。在这里，我们显示钙调神经磷酸酶 Aβ CnAβ-FK 的一种新剪接变体，其由内含子保留的 mRNA 编码，并且缺乏自动抑制结构域，主要在成熟的毛囊角质形成细胞中表达，但不在啮齿动物的增殖角质形成细胞中表达。CnAβ-FK 在角质形成细胞中的低 Ca2+水平下对 Ca2+的敏感性较弱并且 NFATc2 去磷酸化。抑制 Cn/NFAT 在裸鼠中诱导毛发生长。细胞周期蛋白 G2 被鉴定为 Cn/NFATc2 途径的一个新靶标，并且其在毛囊角质形成细胞中的表达通过抑制 Cn/NFAT 而降低。细胞周期蛋白 G2 的过表达在线粒体角质形成细胞中使细胞周期停滞，并且 Cn 抑制剂环孢素 A 抑制 NFATc2 的核定位，导致体内大鼠毛囊角质形成细胞中细胞周期蛋白 G2 的表达减少。因此，我们认为钙调神经磷酸酶/NFAT 途径在毛囊发育中具有独特的调节作用。
