Nakamura Takashi, Yoshitomi Yasuo, Sakai Kiyoshi, Patel Vyomesh, Fukumoto Satoshi, Yamada Yoshihiko
Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan Liaison Center for Innovative Dentistry, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
J Cell Sci. 2014 Dec 15;127(Pt 24):5261-72. doi: 10.1242/jcs.156778. Epub 2014 Oct 24.
The basal layer of the epidermis contains stem cells and transit amplifying cells that rapidly proliferate and differentiate further into the upper layers of the epidermis. A number of molecules have been identified as regulators of this process, including p63 (also known as tumor protein 63) and Notch1. However, little is known about the mechanisms that regulate the transitions from stem cell to proliferating or differentiating transit amplifying cell. Here, we demonstrate that epiprofin (Epfn, also known as Sp6) plays crucial distinct roles in these transition stages as a cell cycle regulator and a transcription factor. Epfn knockout mice have a thickened epidermis, in which p63-expressing basal cells form multiple layers owing to the accumulation of premature transit amplifying cells with reduced proliferation and a reduction in the number of differentiating keratinocytes expressing Notch1. We found that low levels of Epfn expression increased the proliferation of human immortalized keratinocyte (HaCaT) cells by increasing EGF responsiveness and superphosphorylation of Rb. By contrast, high levels of Epfn expression promoted cell cycle exit and differentiation, by reducing E2F transactivation and inducing Notch1 expression. Our findings identify multiple novel functions of Epfn in epidermal development.
表皮的基底层含有干细胞和过渡增殖细胞，这些细胞迅速增殖并进一步分化为表皮的上层细胞。许多分子已被确定为这一过程的调节因子，包括p63（也称为肿瘤蛋白63）和Notch1。然而，对于调节从干细胞到增殖或分化的过渡增殖细胞转变的机制知之甚少。在这里，我们证明表皮蛋白（Epfn，也称为Sp6）作为细胞周期调节因子和转录因子在这些过渡阶段发挥着至关重要的独特作用。Epfn基因敲除小鼠的表皮增厚，其中表达p63的基底细胞形成多层，这是由于过早的过渡增殖细胞积累，增殖减少，以及表达Notch1的分化角质形成细胞数量减少所致。我们发现低水平的Epfn表达通过增加表皮生长因子（EGF）反应性和视网膜母细胞瘤蛋白（Rb）的过度磷酸化来增加人永生化角质形成细胞（HaCaT）的增殖。相比之下，高水平的Epfn表达通过降低E2F反式激活和诱导Notch1表达来促进细胞周期退出和分化。我们的研究结果确定了Epfn在表皮发育中的多种新功能。
