Okuyama Ryuhei, Tagami Hachiro, Aiba Setsuya
Department of Dermatology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
J Dermatol Sci. 2008 Mar;49(3):187-94. doi: 10.1016/j.jdermsci.2007.05.017. Epub 2007 Jul 10.
Skin undergoes self-renewal throughout life. Terminally differentiated keratinocytes, namely the corneocytes, are continually shed from the surface of the skin, whereas immature cells produce progeny that proceed through the differentiation process. Notch signaling controls a number of cellular processes including cell fate decision, proliferation, differentiation and survival/apoptosis. Hence, Notch and its ligands are expressed in multiple tissues including the skin, where they are abundantly expressed in the epidermis. Notch activation results in the promotion of growth arrest and the onset of differentiation, therefore suggesting that specific Notch activation may regulate skin homeostasis by balancing these processes, i.e. Notch signaling functions as a molecular switch that controls the transition of cells between skin layers during the epidermal differentiation process. Recent advances in the study of Notch signaling have confirmed that there is cross-talk between the Notch signaling pathway and a variety of other signaling molecules including Sonic hedgehog (Shh), beta-catenin and the p53 family member, p63. The absence of Notch activity allows Wnt and Shh signaling to persist in a tissue where they are normally repressed. In addition, Notch counteracts the action of p63 to maintain immature cell characteristics. However, aberrant Notch signaling results in the development of psoriasis and skin cancers such as squamous cell carcinoma, basal cell carcinoma and malignant melanoma. Future efforts to further define how Notch controls cell proliferation and differentiation may lead to the application of Notch in new therapies for various skin diseases.
皮肤在整个生命过程中都在进行自我更新。终末分化的角质形成细胞，即角质细胞，不断从皮肤表面脱落，而未成熟细胞产生的后代则经历分化过程。Notch信号传导控制着许多细胞过程，包括细胞命运决定、增殖、分化和存活/凋亡。因此，Notch及其配体在包括皮肤在内的多种组织中表达，在表皮中大量表达。Notch激活导致生长停滞的促进和分化的开始，因此表明特定的Notch激活可能通过平衡这些过程来调节皮肤稳态，即Notch信号传导作为一种分子开关，在表皮分化过程中控制细胞在皮肤层之间的转变。Notch信号传导研究的最新进展证实，Notch信号通路与包括音猬因子（Shh）、β-连环蛋白和p53家族成员p63在内的多种其他信号分子之间存在相互作用。Notch活性的缺失使Wnt和Shh信号在通常被抑制的组织中持续存在。此外，Notch对抗p63的作用以维持未成熟细胞特征。然而，异常的Notch信号传导会导致银屑病和皮肤癌的发生，如鳞状细胞癌、基底细胞癌和恶性黑色素瘤。未来进一步确定Notch如何控制细胞增殖和分化的努力可能会导致Notch在各种皮肤病新疗法中的应用。
