EGFR regulation of epidermal barrier function.
EGFR regulation of epidermal barrier function.
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DOI：
10.1152/physiolgenomics.00176.2011
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发表时间：
2012-04
影响因子：
4.6
通讯作者：
Quynh T. Tran;Lawrence H Kennedy;Sandra Leon Carrion;Sridevi Bodreddigari;S. Goodwin;C. H. Sutter;T. Sutter
中科院分区：
文献类型：
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作者：
Quynh T. Tran;Lawrence H Kennedy;Sandra Leon Carrion;Sridevi Bodreddigari;S. Goodwin;C. H. Sutter;T. Sutter
角质形成细胞终末分化是最终形成哺乳动物生存所必需的表皮屏障的过程。这一过程部分受信号转导和基因表达机制控制，已知表皮生长因子受体（EGFR）是多种表皮功能的重要调节因子。使用融合细胞密度诱导的角质形成细胞分化模型的微阵列分析，我们确定了2，676个受表皮生长因子（EGF）（EGFR的配体）调控的基因。我们进一步发现，并通过功能测定分别证实，EGFR活化通过1）降低脂质基质生物合成酶的表达，2）调节形成皮质包膜的许多基因，和3）抑制紧密连接蛋白的表达，消除了角质形成细胞分化的所有已知的必要过程。在器官型培养的皮肤，表皮生长因子的作用，损害表皮屏障的完整性，增加经表皮水分流失。由于表皮分化缺陷和屏障功能破坏是许多人类皮肤病的主要特征，我们使用生物信息学分析来鉴定已知与皮肤病相关的基因。与非EGF调节基因相比，EGF调节基因显著富集皮肤病基因。这些结果提供了一个系统水平的理解EGFR信号传导抑制角质形成细胞分化的行动，提供了新的见解EGFR失衡的作用，在皮肤发病机制。
Keratinocyte terminal differentiation is the process that ultimately forms the epidermal barrier that is essential for mammalian survival. This process is controlled, in part, by signal transduction and gene expression mechanisms, and the epidermal growth factor receptor (EGFR) is known to be an important regulator of multiple epidermal functions. Using microarray analysis of a confluent cell density-induced model of keratinocyte differentiation, we identified 2,676 genes that are regulated by epidermal growth factor (EGF), a ligand of the EGFR. We further discovered, and separately confirmed by functional assays, that EGFR activation abrogates all of the known essential processes of keratinocyte differentiation by 1) decreasing the expression of lipid matrix biosynthetic enzymes, 2) regulating numerous genes forming the cornified envelope, and 3) suppressing the expression of tight junction proteins. In organotypic cultures of skin, EGF acted to impair epidermal barrier integrity, as shown by increased transepidermal water loss. As defective epidermal differentiation and disruption of barrier function are primary features of many human skin diseases, we used bioinformatic analyses to identify genes that are known to be associated with skin diseases. Compared with non-EGF-regulated genes, EGF-regulated genes were significantly enriched for skin disease genes. These results provide a systems-level understanding of the actions of EGFR signaling to inhibit keratinocyte differentiation, providing new insight into the role of EGFR imbalance in skin pathogenesis.