Keratinocyte differentiation is regulated by the Rho and ROCK signaling pathway
Keratinocyte differentiation is regulated by the Rho and ROCK signaling pathway
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DOI：
10.1016/j.cub.2003.11.050
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发表时间：
2003-12-16
期刊：
影响因子：
9.2
通讯作者：
Hotchin, NA
中科院分区：
文献类型：
--
作者：
McMullan, R;Lax, S;Hotchin, NA
表皮由多层称为角化细胞的特化上皮细胞组成。当细胞从最外层表皮流失时，它们通过末梢分化被取代，在末梢分化中，基底层的角质形成细胞停止增殖，向上迁移，最终到达最外层的角质层。正常的表皮内稳态需要增殖和分化之间的平衡受到严格的调节。GTP结合蛋白RhoA在肌动蛋白细胞骨架的调控和对正常组织稳态至关重要的粘附事件中起着重要作用。RhoA信号的两个中心介质是ROCK丝氨酸/苏氨酸激酶ROCK- i和ROCK- ii[3]。我们分析了ROCK在调节表皮角质形成细胞功能中的作用，方法是使用一种药理学抑制剂，并在原代人角质形成细胞中表达有条件活性或无条件活性的ROCK- ii。我们报道，阻断ROCK功能导致角化细胞终末分化的抑制和细胞增殖的增加。相反，角化细胞中ROCK-II的激活导致细胞周期阻滞和一些与终末分化相关基因的表达增加。因此，这些结果表明ROCK在调节人角质形成细胞增殖和分化之间的平衡中起着关键作用。
The epidermis comprises multiple layers of specialized epithelial cells called keratinocytes. As cells are lost from the outermost epidermal layers, they are replaced through terminal differentiation, in which keratinocytes of the basal layer cease proliferating, migrate upwards, and eventually reach the outermost cornified layers. Normal homeostasis of the epidermis requires that the balance between proliferation and differentiation be tightly regulated [1]. The GTP binding protein RhoA plays a fundamental role in the regulation of the actin cytoskeleton and in the adhesion events that are critically important to normal tissue homeostasis [2]. Two central mediators of the signals from RhoA are the ROCK serine/threonine kinases ROCK-I and ROCK-II [3]. We have analyzed ROCK's role in the regulation of epidermal keratinocyte function by using a pharmacological inhibitor and expressing conditionally active or inactive forms of ROCK-II in primary human keratinocytes. We report that blocking ROCK function results in inhibition of keratinocyte terminal differentiation and an increase in cell proliferation. In contrast, activation of ROCK-II in keratinocytes results in cell cycle arrest and an increase in the expression of a number of genes associated with terminal differentiation. Thus, these results indicate that ROCK plays a critical role in regulating the balance between proliferation and differentiation in human keratinocytes.