Drosten Matthias, Lechuga Carmen G, Barbacid Mariano
Molecular Oncology Programme; Centro Nacional de Investigaciones Oncológicas (CNIO); Madrid, Spain.
Small GTPases. 2013 Oct-Dec;4(4):236-41. doi: 10.4161/sgtp.26905. Epub 2013 Oct 22.
Proliferation and differentiation of epidermal keratinocytes are tightly controlled to ensure proper development and homeostasis of the epidermis. The Ras family of small GTPases has emerged as a central node in the coordination of cell proliferation in the epidermis. Recent genetic evidence from mouse models has revealed that the intensity of Ras signaling modulates the proliferative capacity of epidermal keratinocytes. Interfering with Ras signaling either by combined elimination of the 3 Ras genes from the basal layer of the epidermis or by overexpression of dominant-negative Ras isoforms caused epidermal thinning due to hypoproliferation of keratinocytes. In contrast, overexpression of oncogenic Ras mutants in different epidermal cell layers led to hyperproliferative phenotypes including the development of papillomas and squamous cell carcinomas. Here, we discuss the value of loss- and gain-of-function studies in mouse models to assess the role of Ras signaling in the control of epidermal proliferation.
表皮角质形成细胞的增殖和分化受到严格调控，以确保表皮的正常发育和稳态。小GTP酶的Ras家族已成为表皮细胞增殖协调中的一个核心节点。来自小鼠模型的最新遗传学证据表明，Ras信号的强度调节表皮角质形成细胞的增殖能力。通过从表皮基底层联合消除3个Ras基因或通过显性负性Ras异构体的过表达来干扰Ras信号，会因角质形成细胞增殖不足而导致表皮变薄。相反，在不同表皮细胞层中过表达致癌性Ras突变体则导致过度增殖表型，包括乳头状瘤和鳞状细胞癌的发生。在此，我们讨论在小鼠模型中进行功能丧失和功能获得研究以评估Ras信号在控制表皮增殖中的作用的价值。
